Cot modulators and methods of use thereof

ABSTRACT

The present disclosure relates generally to modulators of Cot (cancer Osaka thyroid) and methods of use and manufacture thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. 119(e) to U.S.Provisional Application No. 62/189,158, filed Jul. 6, 2015, and U.S.Provisional Application No. 62/269,060, filed Dec. 17, 2015, where thecontents of each is incorporated herein by reference in its entirety.

FIELD

The present disclosure relates generally to modulators of Cot (cancerOsaka thyroid) and methods of use and manufacture thereof.

BACKGROUND

Cot (cancer Osaka thyroid) protein is a serine/threonine kinase that isa member of the MAP kinase kinase kinase (MAP3K) family. It is alsoknown as “Tp12” (tumor progression locus), “MAP3K8” (mitogen-activatedprotein kinase kinase kinase 8) or “EST” (Ewing sarcoma transformant).Cot was identified by its oncogenic transforming activity in cells andhas been shown to regulate oncogenic and inflammatory pathways.

Cot is known to be upstream in the MEK-ERK pathway and is essential forLPS induced tumor necrosis factor-α (TNF-α) production. Cot has beenshown to be involved in both production and signaling of TNFα. TNFα is apro-inflammatory cytokine and plays an important role in inflammatorydiseases, such as rheumatoid arthritis (RA), multiple sclerosis (MS),inflammatory bowel disease (IBD), diabetes, sepsis, psoriasis,misregulated TNFα expression and graft rejection.

Agents and methods that modulate the expression or activity of Cot,therefore, may be useful for preventing or treating such diseases.

SUMMARY

The present disclosure provides compounds that modulate the expressionor activity of Cot. The disclosure also provides compositions, includingpharmaceutical compositions, kits that include the compounds, andmethods of using (or administering) and making the compounds. Thecompounds provided herein are useful in treating diseases, disorders, orconditions that are mediated by Cot. The disclosure also providescompounds for use in therapy. The disclosure further provides compoundsfor use in a method of treating a disease, disorder, or condition thatis mediated by Cot. Moreover, the disclosure provides uses of thecompounds in the manufacture of a medicament for the treatment of adisease, disorder or condition that is mediated by (or meadiated, atleast in part, by) Cot.

In one aspect, provided is a compound having the structure of Formula I:

whereinR¹ is hydrogen, —O—R⁷, —N(R⁸)(R⁹), —C(O)—R⁷, —S(O)₂—R⁷, —C₁₋₉ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, orheteroaryl;

-   -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally        substituted with one to four Z¹;        R² is hydrogen, —C(O)—R⁷, —C(O)O—R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z²;        or R¹ and R² together with the nitrogen to which they are        attached to form a heterocyclyl or heteroaryl, wherein each        heterocyclyl or heteroaryl is optionally substituted with one to        four Z²;        R³ is heterocyclyl or heteroaryl, wherein each heterocyclyl or        heteroaryl is optionally substituted with one to four Z³;        R⁴ is heterocyclyl or heteroaryl, wherein each heterocyclyl or        heteroaryl is optionally substituted with one to four Z⁴;

-   R⁵ is hydrogen, halo, —CN, —NO₂, —N(R⁸)(R⁹), —S(O)—R⁷, —S(O)₂R⁷,    —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷, —OC(O)O—R⁷,    —OC(O)N(R¹⁰)(R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆ haloalkyl, C₃₋₁₅    cycloalkyl, aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉        alkylthio, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl,        and heteroaryl may be optionally substituted with one to four        Z⁵;        R⁶ is hydrogen, —C(O)—R⁷, —C(O)O—R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z⁶;        each R⁷ is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,        heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z⁷;        R⁸ and R⁹ at each occurrence are independently hydrogen,        —S(O)₂R¹⁰, —C(O)—R¹⁰, —C(O)O—R¹⁰, —C(O)N(R¹⁰ (R¹¹), C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl        may be optionally substituted with one to four Z⁸;        R¹⁰ and R¹¹ at each occurrence are independently hydrogen, C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅        cycloalkyl, aryl, heterocyclyl, or heteroaryl,    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        optionally is substituted with one to four Z¹⁶;        each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, and Z⁸ is independently        hydrogen, oxo, halo, —NO₂, —N₃, —CN, thioxo, C₁₋₉ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl,        heteroaryl, heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹²,        —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,        —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹³)(R¹⁴),        —N(R¹²)S(O)₂(R¹²)⁺, —NR¹²S(O)₂N(R¹³)(R¹⁴), —NR¹²S(O)₂O(R¹²),        —OC(O)R¹², —OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂, —OP(O)(OR¹²)₂,        —CH₂P(O)(OR¹²)₂, —OCH₂P(O)(OR¹²)₂, —C(O)OCH₂P(O)(OR¹²)₂,        —P(O)(R¹²)(OR¹²), —OP(O)(R¹²)(OR¹²), —CH₂P(O)(R¹²)(OR¹²),        —OCH₂P(O)(R¹²)(OR¹²), —C(O)OCH₂P(O)(R¹²)(OR¹²), —P(O)(N(R¹²)₂)₂,        —OP(O)(N(R¹²)₂)₂, —CH₂P(O)(N(R¹²)₂)₂, —OCH₂P(O)(N(R¹²)₂)₂,        —C(O)OCH₂P(O)(N(R¹²)₂)₂, —P(O)(N(R¹²)₂)(OR¹²),        —OP(O)(N(R¹²)₂)(OR¹²), —CH₂P(O)(N(R¹²)₂)(OR¹²),        —OCH₂P(O)(N(R¹²)₂)(OR¹²), —C(O)OCH₂P(O)(N(R¹²)₂)(OR¹²),        —P(O)(R¹²)(NR¹²)₂), —OP(O)(R¹²)(N(R¹²)₂),        —CH₂P(O)(R¹²)(N(R¹²)₂), —OCH₂P(O)(R¹²)(N(R¹²)₂),        —C(O)OCH₂P(O)(R¹²)(N(R¹²)₂), —Si(R¹²)₃, —S—R¹², —S(O)R¹²,        —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl,        aryl, heteroaryl or heterocyclyl is optionally substituted with        one to four Z^(1a) groups;        each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈        haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹²,        —C(O)O—R¹², —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,        —N(R¹²)—C(O)R¹², —N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹³)(R¹⁴),        —N(R¹²)S(O)₂(R¹²), —N(R¹²)S(O)₂—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂O(R¹²),        —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹³)(R¹⁴), —Si(R¹²)₃, —S—R¹²,        —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        each R¹² is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or        heterocyclyl,    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        R¹³ and R¹⁴ at each occurrence are each independently hydrogen,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl,        heteroaryl or heterocyclyl;    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups, or R¹³ and R¹⁴ together with the nitrogen to        which they are attached form a heterocyclyl, wherein said        heterocyclyl is optionally substituted with one to four Z^(1b)        groups;        each R¹⁵ is independently halo, —CN, —NO₂, —O—R⁷, —N(R⁸)(R⁹),        —S(O)—R⁷, —S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷,        —OC(O)O—R⁷, —OC(O)N(R¹⁰ (R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl;        and        each Z^(1b) is independently oxo, thioxo, hydroxy, halo, —NO₂,        —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl,        —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅        cycloalkyl), haloalkyl), —O(aryl), —O(heteroaryl),        —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl),        —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₉ haloalkyl),        —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), alkyl)₂, —N(C₃₋₁₅        cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅        cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,        —N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), alkyl)(C₂₋₆        alkenyl), alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅        cycloalkyl), alkyl)(C₁₋₈ haloalkyl), alkyl)(aryl),        alkyl)(heteroaryl), alkyl)(heterocyclyl), —C(O)(C₁₋₉ alkyl),        —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅        cycloalkyl), —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl),        —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl),        —C(O)O(C₂₋₆ alkenyl), —C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅        cycloalkyl), —C(O)O(C₁₋₈ haloalkyl), —C(O)O(aryl),        —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂, —C(O)NH(C₁₋₉        alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),        —C(O)NH(C₃₋₁₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl),        —C(O)NH(aryl), —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl),        —C(O)N(C₁₋₉ alkyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆        alkenyl)₂, —C(O)N(C₂₋₆ alkynyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂,        —C(O)N(C₁₋₈ haloalkyl)₂, —C(O)N(aryl)₂, —C(O)N(heteroaryl)₂,        —C(O)N(heterocyclyl)₂, —NHC(O)(C₁₋₉ alkyl), —NHC(O)(C₂₋₆        alkenyl), —NHC(O)(C₂₋₆ alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl),        —NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),        —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆        alkenyl), —NHC(O)O(C₂-6 alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),        —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),        —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆        alkenyl), —NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl),        —NHC(O)NH(C₁₋₈ haloalkyl), —NHC(O)NH(aryl),        —NHC(O)NH(heteroaryl), —NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉        alkyl), —S(C₂₋₆ alkenyl), —S(C₂₋₆ alkynyl), —S(C₃₋₁₅        cycloalkyl), haloalkyl), —S(aryl), —S(heteroaryl),        —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl), —N(C₁₋₉ alkyl)(S(O)(C₁₋₉        alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉        alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆ alkynyl), —S(O)(C₃₋₁₅        cycloalkyl), —S(O)(C haloalkyl), —S(O)(aryl), —S(O)(heteroaryl),        —S(O)(heterocyclyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₂₋₆ alkenyl),        —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈        haloalkyl), —S(O)₂(aryl), —S(O)₂(heteroaryl),        —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl), or —S(O)₂N(C₁₋₉        alkyl)₂;    -   wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl        is optionally substituted with one to four halo, C₁₋₉ alkyl,        C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉ alkyl), —NH(C₃₋₁₅        cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl), —NH(heteroaryl),        —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅ cycloalkyl)₂,        —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C haloalkyl), —NHC(O)(aryl),        —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉        alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),        —NHC(O)O(C haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),        —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉        alkyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C        haloalkyl), —S(O)₂(aryl), —S(O)₂(heteroaryl),        —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl), —S(O)₂N(C₁₋₉        alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl),        —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl); and        m is 0, 1, or 2;        or a pharmaceutically acceptable salt, tautomer, stereoisomer,        mixture of stereoisomers, prodrug, or deuterated analog thereof.

Some embodiments provide a method of using (or administering) thecompounds of Formula I, or additional Formula(s) described throughout,in the treatment of a disease or condition in a mammal, particularly ahuman, that is amenable to treatment by an Cot modulator.

In certain embodiments, the disclosure provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof the disclosure (e.g. a compound of Formula I or additional Formulasdescribed throughout), and at least one pharmaceutically acceptableexcipient.

DETAILED DESCRIPTION Definitions and General Parameters

The following description sets forth exemplary methods, parameters andthe like. It should be recognized, however, that such description is notintended as a limitation on the scope of the present disclosure but isinstead provided as a description of exemplary embodiments.

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —C(O)NH₂is attached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or named.

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to8 carbon atoms (i.e., C₁₋₃ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆,alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having aspecific number of carbons is named by chemical name or identified bymolecular formula, all positional isomers having that number of carbonsmay be encompassed; thus, for example, “butyl” includes n-butyl (i.e.—(CH₂)₃CH₃), sec-butyl (i.e. —CH(CH₃)CH₂CH₃), isobutyl (i.e.—CH₂CH(CH₃)₂) and tert-butyl (i.e. —C(CH₃)₃); and “propyl” includesn-propyl (i.e. —(CH₂)₂CH₃) and isopropyl (i.e. —CH(CH₃)₂).

“Alkenyl” refers to an alkyl group containing at least one carbon-carbondouble bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkenyl),2 to 8 carbon atoms C₂₋₈ alkenyl), 2 to 6 carbon atoms (i.e., C₂₋₆alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl). Examples ofalkenyl groups include ethenyl, propenyl, butadienyl (including1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an alkyl group containing at least one carbon-carbontriple bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkynyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl). The term“alkynyl” also includes those groups having one triple bond and onedouble bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

“Haloalkoxy” refers to an alkoxy group as defined above, wherein one ormore hydrogen atoms are replaced by a halogen.

“Alkylthio” refers to the group “alkyl-S—”.

“Acyl” refers to a group —C(O)R, wherein R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein. Examples of acylinclude formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl,and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(O)NR^(y)R^(z) and an “N-amido” group which refers to the group—NR^(y)C(O)R^(z), wherein R^(y) and R^(z) are independently selectedfrom the group consisting of hydrogen, alkyl, aryl, haloalkyl, orheteroaryl; each of which may be optionally substituted.

“Amino” refers to the group —NR^(y)R^(z) wherein R^(y) and R^(z) areindependently selected from the group consisting of hydrogen, alkyl,haloalkyl, aryl, or heteroaryl; each of which may be optionallysubstituted.

“Amidino” refers to —C(NH)(NH₂).

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, doesnot encompass or overlap in any way with heteroaryl defined below. Ifone or more aryl groups are fused with a heteroaryl, the resulting ringsystem is heteroaryl. If one or more aryl groups are fused with aheterocyclyl, the resulting ring system is heterocyclyl.

“Azido” refers to —N₃.

“Carbamoyl” refers to both an “O-carbamoyl” group which refers to thegroup —O—C(O)NR^(y)R^(z) and an “N-carbamoyl” group which refers to thegroup —NR^(y)C(O)OR^(z), wherein R^(y) and R^(z) are independentlyselected from the group consisting of hydrogen, alkyl, aryl, haloalkyl,or heteroaryl; each of which may be optionally substituted.

“Carboxyl” refers to —C(O)OH.

“Carboxyl ester” refers to both —OC(O)R and —C(O)OR, wherein R ishydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e. the cyclic group having at least one double bond). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Guanidino” refers to —NHC(NH)(NH₂).

“Hydrazino” refers to —NHNH₂.

“Imino” refers to a group —C(NR)R, wherein each R is alkyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Halogen” or “halo” includes fluoro, chloro, promo, and iodo.“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

“Heteroalkyl” refers to an alkyl group in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group. The term“heteroalkyl” includes unbranched or branched saturated chain havingcarbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may beindependently replaced with the same or different heteroatomic group.Heteroatomic groups include, but are not limited to, —NR—, —O—, —S—,—S(O)—, —S(O)₂—, and the like, where R is H, alkyl, aryl, cycloalkyl,heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionallysubstituted. Examples of heteroalkyl groups include —OCH₃, —CH₂OCH₃,—SCH₃, —CH₂SCH₃, —NRCH₃, and —CH₂NRCH₃, where R is hydrogen, alkyl,aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may beoptionally substituted. As used herein, heteroalkyl include 1 to 10carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C₁₋₂₀heteroaryl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heteroaryl), or 3 to8 carbon ring atoms (i.e., C₃₋₈ heteroaryl); and 1 to 5 heteroatoms, 1to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1ring heteroatom independently selected from nitrogen, oxygen, andsulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl,pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of thefused-heteroaryl rings include, but are not limited to,benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl,indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, andimidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via eitherring of the fused system. Any aromatic ring, having a single or multiplefused rings, containing at least one heteroatom, is considered aheteroaryl regardless of the attachment to the remainder of the molecule(i.e., through any one of the fused rings). Heteroaryl does notencompass or overlap with aryl as defined above.

“Heterocyclyl” refers to a saturated or unsaturated cyclic alkyl group,with one or more ring heteroatoms independently selected from nitrogen,oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenylgroups (i.e. the heterocyclyl group having at least one double bond),bridged-heterocyclyl groups, fused-heterocyclyl groups, andspiro-heterocyclyl groups. A heterocyclyl may be a single ring ormultiple rings wherein the multiple rings may be fused, bridged, orspiro. Any non-aromatic ring containing at least one heteroatom isconsidered a heterocyclyl, regardless of the attachment (i.e., can bebound through a carbon atom or a heteroatom). Further, the termheterocyclyl is intended to encompass any non-aromatic ring containingat least one heteroatom, which ring may be fused to an aryl orheteroaryl ring, regardless of the attachment to the remainder of themolecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms(i.e., C₂₋₂₀ heterocyclyl), 2 to 12 ring carbon atoms (i.e., C₂₋₁₂heterocyclyl), 2 to 10 ring carbon atoms (i.e., C₂₋₁₀ heterocyclyl), 2to 8 ring carbon atoms (i.e., C₂₋₈ heterocyclyl), 3 to 12 ring carbonatoms (i.e., C₃₋₁₂ heterocyclyl), 3 to 8 ring carbon atoms (i.e., C₃₋₈heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆ heterocyclyl);having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ringheteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independentlyselected from nitrogen, sulfur or oxygen. A heterocyclyl may contain oneor more oxo and/or thioxo groups. Examples of heterocyclyl groupsinclude pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl,azetidinyl, and morpholinyl. As used herein, the term“bridged-heterocyclyl” refers to a four- to ten-membered cyclic moietyconnected at two non-adjacent atoms of the heterocyclyl with one or more(e.g. 1 or 2) four- to ten-membered cyclic moiety having at least oneheteroatom where each heteroatom is independently selected fromnitrogen, oxygen, and sulfur. As used herein, bridged-heterocyclylincludes bicyclic and tricyclic ring systems. Also used herein, the term“spiro-heterocyclyl” refers to a ring system in which a three- toten-membered heterocyclyl has one or more additional ring, wherein theone or more additional ring is three- to ten-membered cycloalkyl orthree- to ten-membered heterocyclyl, where a single atom of the one ormore additional ring is also an atom of the three- to ten-memberedheterocyclyl. Examples of the spiro-heterocyclyl rings include bicyclicand tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl,2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl.Examples of the fused-heterocyclyl rings include, but are not limitedto, 1,2,3,4-tetrahydroisoquinolinyl,1-oxo-1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl,4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl,where the heterocyclyl can be bound via either ring of the fused system.

“Hydroxy” or “hydroxyl” refers to the group —OH. “Hydroxyalkyl” refersto an unbranched or branched alkyl group as defined above, wherein oneor more hydrogen atoms are replaced by a hydroxyl.

“Oxo” refers to the group (═O) or (O).

“Nitro” refers to the group —NO₂.

“Sulfonyl” refers to the group —S(O)₂R, where R is alkyl, haloalkyl,heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl aremethylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

“Alkylsulfonyl” refers to the group —S(O)₂R, where R is alkyl.

“Alkylsulfinyl” refers to the group —S(O)R, where R is alkyl.

“Thiocyanate”—SCN.

“Thiol” refers to the group —SR, where R is alkyl, haloalkyl,heterocyclyl, cycloalkyl, heteroaryl, or aryl.

“Thioxo” or “thione” refer to the group (═S) or (S).

Certain commonly used alternative chemical names may be used. Forexample, a divalent group such as a divalent “alkyl” group, a divalent“aryl” group, etc., may also be referred to as an “alkylene” group or an“alkylenyl” group, an “arylene” group or an “arylenyl” group,respectively. Also, unless indicated explicitly otherwise, wherecombinations of groups are referred to herein as one moiety, e.g.arylalkyl, the last mentioned group contains the atom by which themoiety is attached to the rest of the molecule.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen.

Some of the compounds exist as tautomers. Tautomers are in equilibriumwith one another. For example, amide containing compounds may exist inequilibrium with imidic acid tautomers. Regardless of which tautomer isshown, and regardless of the nature of the equilibrium among tautomers,the compounds are understood by one of ordinary skill in the art tocomprise both amide and imidic acid tautomers. Thus, the amidecontaining compounds are understood to include their imidic acidtautomers. Likewise, the imidic acid containing compounds are understoodto include their amide tautomers.

Any formula or structure given herein, is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labelled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also includes “deuterated analogues” of compounds ofFormula I in which from 1 to n hydrogens attached to a carbon atomis/are replaced by deuterium, in which n is the number of hydrogens inthe molecule. Such compounds exhibit increased resistance to metabolismand are thus useful for increasing the half-life of any compound ofFormula I when administered to a mammal, particularly a human. See, forexample, Foster, “Deuterium Isotope Effects in Studies of DrugMetabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compoundsare synthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound of Formula I.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, polymorphs, and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.“Pharmaceutically acceptable salts” or “physiologically acceptablesalts” include, for example, salts with inorganic acids and salts withan organic acid. In addition, if the compounds described herein areobtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid salt. Conversely, if the product is afree base, an addition salt, particularly a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare nontoxic pharmaceuticallyacceptable addition salts. Pharmaceutically acceptable acid additionsalts may be prepared from inorganic and organic acids. Salts derivedfrom inorganic acids include hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derivedfrom organic acids include acetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluene-sulfonic acid, salicylic acid, and the like. Likewise,pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines (i.e., NH₂(alkyl)), dialkyl amines (i.e., HN(alkyl)₂),trialkyl amines (i.e., N(alkyl)₃), substituted alkyl amines (i.e.,NH₂(substituted alkyl)), di(substituted alkyl) amines (i.e.,HN(substituted alkyl)₂), tri(substituted alkyl) amines (i.e.,N(substituted alkyl)₃), alkenyl amines (i.e., NH₂(alkenyl)), dialkenylamines (i.e., HN(alkenyl)₂), trialkenyl amines (i.e., N(alkenyl)₃),substituted alkenyl amines (i.e., NH₂(substituted alkenyl)),di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)₂),tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)₃, mono-,di- or tri-cycloalkyl amines (i.e., NH₂(cycloalkyl), HN(cycloalkyl)₂,N(cycloalkyl)₃), mono-, di- or tri-arylamines (i.e., NH₂(aryl),HN(aryl)₂, N(aryl)₃), or mixed amines, etc. Specific examples ofsuitable amines include, by way of example only, isopropylamine,trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy,hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid,alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.Polymers or similar indefinite structures arrived at by definingsubstituents with further substituents appended ad infinitum (e.g., asubstituted aryl having a substituted alkyl which is itself substitutedwith a substituted aryl group, which is further substituted by asubstituted heteroalkyl group, etc.) are not intended for inclusionherein. Unless otherwise noted, the maximum number of serialsubstitutions in compounds described herein is three. For example,serial substitutions of substituted aryl groups with two othersubstituted aryl groups are limited to ((substituted aryl)substitutedaryl) substituted aryl. Similarly, the above definitions are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluorines or heteroaryl groups having two adjacentoxygen ring atoms). Such impermissible substitution patterns are wellknown to the skilled artisan. When used to modify a chemical group, theterm “substituted” may describe other chemical groups defined herein.Unless specified otherwise, where a group is described as optionallysubstituted, any substituents of the group are themselves unsubstituted.For example, in some embodiments, the term “substituted alkyl” refers toan alkyl group having one or more substituents including hydroxyl, halo,alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In otherembodiments, the one or more substituents may be further substitutedwith halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is substituted. In other embodiments,the substituents may be further substituted with halo, alkyl, haloalkyl,alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each ofwhich is unsubstituted.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds described herein are also provided.Hydrates of the compounds described herein are also provided.

LIST OF ABBREVIATIONS AND ACRONYMS

Abbreviation Meaning ° C. Degree Celsius Ac Acetyl aq. Aqueous ATPAdenosine triphosphate BOC tert-Butoxycarbonyl br Broad BSA Bovine serumalbumin Cbz Carboxybenzyl COD Cyclooctadiene COPD Chronic obstructivepulmonary disease Cot Cancer Osaka Thyroid Cp Cyclopentadienyl d DoubletDABCO 1,4-Diazabicyclo[2.2.2]octane DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DCE Dichloroethene DCMDichloromethane dd Doublet of doublets DEF N,N-Diethylformamide DMFDimethylformamide DMSO Dimethylsulfoxide dppf1,1′-Bis(diphenylphosphino)ferrocene dt Doublet-triplet DTTDithiothreitol EC₅₀ The half maximal effective concentration EGFREpidermal growth factor receptor eq Equivalents ES/MS Electrospray massspectrometry Et Ethyl FBS Fetal bovine serum g Grams HEPES2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid HPLC Highpressure liquid chromatography hrs Hours Hz Hertz IBD Inflammatory boweldisease i-pr Isopropyl J Coupling constant (MHz) Kg/kg Kilogram LCMSLiquid chromatography-mass spectrometry LPS Lipopolysaccharide M Molar mmultiplet M+ Mass peak M + H+ Mass peak plus hydrogen Me Methyl mgMilligram MHz Megahertz min Minute ml/mL Milliliter mM Millimolar mmolMillimole MOPS 3-Morpholinopropane-1-sulfonic acid MS Mass spectroscopyMs Mesyl nBu/Bu Butyl nL Nanoliter nm Nanometer NMR Nuclear magneticresonance NP-40 Nonyl phenoxypolyethoxylethanol Ns Nosyl Pd-C/Pd/CPalladium on Carbon pg Pictogram Ph Phenyl PPTS Pyridiniump-toluenesulfonate PS Polystyrene p-TSOH/pTSA p-Toluenesulfonic acid qQuartet q.s. Quantity sufficient to achieve a stated function RBF Roundbottom flask RP Reverse phase RPMI Roswell Park Memorial Institutemedium rt Room temperature s Singlet sat. Saturated t Triplet TBAFTetra-n-butylammonium fluoride TBS tert-Butyldimethylsilyl t-Butert-Butyl TC Thiophene-2-carboxylate TEA Triethanolamine TfTrifluoromethanesulfonyl TFA Trifluoroacetic acid THF TetrahydrofuranTpl2 Tumor Progression Locus 2 TR-FRET Time-resolved fluorescence energytransfer Ts Tosyl δ Chemical shift (ppm) μL/μl Microliter μM Micromolar

Compounds

Provided herein are compounds that function as modulators of Cot. In oneaspect, provided is a compound having structure of Formula I:

whereinR¹ is hydrogen, —O—R⁷, —N(R⁸)(R⁹), —C(O)—R⁷, —S(O)₂—R⁷, —C₁₋₉ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, orheteroaryl;

-   -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally        substituted with one to four Z¹;        R² is hydrogen, —C(O)—R⁷, —C(O)O—R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z²;        or R¹ and R² together with the nitrogen to which they are        attached to form a heterocyclyl or heteroaryl, wherein each        heterocyclyl or heteroaryl is optionally substituted with one to        four Z²;        R³ is heterocyclyl or heteroaryl, wherein each heterocyclyl or        heteroaryl is optionally substituted with one to four Z³;        R⁴ is heterocyclyl or heteroaryl, wherein each heterocyclyl or        heteroaryl is optionally substituted with one to four Z⁴;        R⁵ is hydrogen, halo, —CN, —NO₂, —O—R⁷, —N(R⁸)(R⁹), —S(O)—R⁷,        —S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷,        —OC(O)O—R⁷, —OC(O)N(R¹⁰)(R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉        alkylthio, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl,        and heteroaryl may be optionally substituted with one to four        Z⁵;        R⁶ is hydrogen, —C(O)—R⁷, —C(O)O—R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z⁶;        each R⁷ is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,        heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z⁷;        R⁸ and R⁹ at each occurrence are independently hydrogen,        —S(O)₂R¹⁰, —C(O)—R¹⁰, —C(O)O—R¹⁰, —C(O)N(R¹⁰)(R¹¹), C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl        may be optionally substituted with one to four Z⁸;        R¹⁰ and R¹¹ at each occurrence are independently hydrogen, C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅        cycloalkyl, aryl, heterocyclyl, or heteroaryl,    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        optionally is substituted with one to four Z¹⁶;        each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, and Z⁸ is independently        hydrogen, oxo, halo, —NO₂, —N₃, —CN, thioxo, C₁₋₉ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl,        heteroaryl, heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹²,        —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,        —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹³)(R¹⁴),        —N(R¹²)S(O)₂(R¹²), —NR¹²S(O)₂N(R¹³)(R¹⁴), —NR¹²S(O)₂O(R¹²),        —OC(O)R¹², —OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂, —OP(O)(OR¹²)₂,        —CH₂P(O)(OR¹²)₂, —OCH₂P(O)(OR¹²)₂, —C(O)OCH₂P(O)(OR¹²)₂,        —P(O)(R¹²)(OR¹²), —OP(O)(R¹²)(OR¹²), —CH₂P(O)(R¹²)(OR¹²),        —OCH₂P(O)(R¹²)(OR¹²), —C(O)OCH₂P(O)(R¹²)(OR¹²), —P(O)(N(R¹²)₂)₂,        —OP(O)(N(R¹²)₂)₂, —CH₂P(O)(N(R¹²)₂)₂, —OCH₂P(O)(N(R¹²)₂)₂,        —C(O)OCH₂P(O)(N(R¹²)₂)₂, —P(O)(N(R¹²)₂)(OR¹²),        —OP(O)(N(R¹²)₂)(OR¹²), —CH₂P(O)(N(R¹²)₂)(OR¹²),        —OCH₂P(O)(NR¹²)₂)(OR¹²), —C(O)OCH₂P(O)(N(R¹²)₂)(OR¹²),        —P(O)(R¹²)(NR¹²)₂), —OP(O)(R¹²)(N(R¹²)₂), —CH₂P(O)(R¹²)(NR¹²)₂),        —OCH₂P(O)(R¹²)(NR¹²)₂), —C(O)OCH₂P(O)(R¹²)(N(R¹²)₂), —Si(R¹²)₃,        —S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl,        aryl, heteroaryl or heterocyclyl is optionally substituted with        one to four Z^(1a) groups;        each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈        haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹²,        —C(O)O—R¹², —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,        —N(R¹²)—C(O)R¹², —N(R¹²)C(O)O(R¹²), —N(R¹²)S(O)₂(R¹²),        —N(R¹²)S(O)₂—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂O(R¹²), —OC(O)R¹²,        —OC(O)OR¹², —OC(O)—N(R¹³)(R¹⁴), —Si(R¹²)₃, —S—R¹², —S(O)R¹²,        —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        each R¹² is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or        heterocyclyl,    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        R¹³ and R¹⁴ at each occurrence are each independently hydrogen,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl,        heteroaryl or heterocyclyl;    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups, or R¹³ and R¹⁴ together with the nitrogen to        which they are attached form a heterocyclyl, wherein said        heterocyclyl is optionally substituted with one to four Z^(1b)        groups;        each R¹⁵ is independently halo, —CN, —NO₂, —O—R⁷, —N(R⁸)(R⁹),        —S(O)—R⁷, —S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷,        —OC(O)O—R⁷, —OC(O)N(R¹⁰)(R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl;        each Z^(1b) is independently oxo, thioxo, hydroxy, halo, —NO₂,        —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl,        —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅        cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl), —O(heteroaryl),        —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl),        —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl),        —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂,        —N(C₃₋₁₅ cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂,        —N(C₃₋₁₅ cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂,        —N(heteroaryl)₂, —N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅        cycloalkyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆        alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈        haloalkyl), —N(C₁₋₉ alkyl)(aryl), —N(C₁₋₉ alkyl)(heteroaryl),        —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉ alkyl), —C(O)(C₂₋₆        alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅ cycloalkyl),        —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl), —C(O)(heteroaryl),        —C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl), —C(O)O(C₂₋₆ alkenyl),        —C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅ cycloalkyl), —C(O)O(C₁₋₈        haloalkyl), —C(O)O(aryl), —C(O)O(heteroaryl),        —C(O)O(heterocyclyl), —C(O)NH₂, —C(O)NH(C₁₋₉ alkyl),        —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl), —C(O)NH(C₃₋₁₅        cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl), —C(O)NH(aryl),        —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,        —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆        alkynyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂,        —C(O)N(aryl)₂, —C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂,        —NHC(O)(C₁₋₉ alkyl), —NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆        alkynyl), —NHC(O) (C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl), —NHC(O)O(C₂₋₆        alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl),        —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl),        —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl), —NHC(O)NH(C₂₋₆        alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈        haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),        —NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl), —S(C₂₋₆ alkenyl),        —S(C₂₋₆ alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈ haloalkyl),        —S(aryl), —S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl),        —N(C₁₋₉ alkyl)(S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆        alkynyl), —S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁₋₈ haloalkyl),        —S(O)(aryl), —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉        alkyl), —S(O)₂(C₂₋₆ alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        or —S(O)₂N(C₁₋₉ alkyl)₂;    -   wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl        is optionally substituted with one to four halo, C₁₋₉ alkyl,        C₁₋₉ haloalkyl, —OH, —NH₂, —NH(C₁₋₉ alkyl), —NH(C₃₋₁₅        cycloalkyl), —NH(C₁₋₉ haloalkyl), —NH(aryl), —NH(heteroaryl),        —NH(heterocyclyl), alkyl)₂, —N(C₃₋₁₅ cycloalkyl)₂, —NHC(O)(C₃₋₁₅        cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl),        —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉        alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),        —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),        —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉        alkyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅ cycloalkyl),        —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl), —S(O)₂(heteroaryl),        —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl), —S(O)₂N(C₁₋₉        alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl),        —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl); and        m is 0, 1, or 2;        or a pharmaceutically acceptable salt, tautomer, stereoisomer,        mixture of stereoisomers, prodrug, or deuterated analog thereof.

In another aspect, provided is a compound having structure of Formula I:

whereinR¹ is hydrogen, —O—R⁷, —N(R⁸)(R⁹), —C(O)—R⁷, —S(O)₂—R⁷, —C₁₋₉ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, orheteroaryl;

-   -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally        substituted with one to four Z¹;        R² is hydrogen, —C(O)—R⁷, —C(O)O—R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z²;        or R¹ and R² together with the nitrogen to which they are        attached to form a heterocyclyl or heteroaryl, wherein each        heterocyclyl or heteroaryl is optionally substituted with one to        four Z²;        R³ is heterocyclyl or heteroaryl, wherein each heterocyclyl or        heteroaryl is optionally substituted with one to four Z³;        R⁴ is heterocyclyl or heteroaryl, wherein each heterocyclyl or        heteroaryl is optionally substituted with one to four Z⁴;        R⁵ is hydrogen, halo, —CN, —NO₂, —O—R⁷, —N(R⁸)(R⁹), —S(O)—R⁷,        —S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷,        —OC(O)O—R⁷, —OC(O)N(R¹⁰ (R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉        alkylthio, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl,        and heteroaryl may be optionally substituted with one to four        Z⁵;        R⁶ is hydrogen, —C(O)—R⁷, —C(O)O—R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z⁶;        each R⁷ is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,        heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z⁷;        R⁸ and R⁹ at each occurrence are independently hydrogen,        —S(O)₂R¹⁰, —C(O)—R¹⁰, —C(O)O—R¹⁰, —C(O)N(R¹⁰ (R¹¹), C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, haloalkyl,        C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl may be        optionally substituted with one to four Z⁸;        R¹⁰ and R¹¹ at each occurrence are independently hydrogen, C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅        cycloalkyl, aryl, heterocyclyl, or heteroaryl,    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, haloalkyl,        C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl optionally        is substituted with one to four Z^(1b);        each Z¹, Z², Z³, Z⁴, Z⁵ ₉ Z⁶, Z⁷, and Z⁸ is independently        hydrogen, oxo, halo, —NO₂, —N₃, —CN, thioxo, C₁₋₉ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl,        heteroaryl, heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹²,        —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,        —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹³)(R¹⁴),        —N(R¹²)S(O)₂(R¹²), —NR¹²S(O)₂N(R¹³)(R¹⁴), —NR¹²S(O)₂O(R¹²),        —OC(O)R¹², —OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂, —OP(O)(OR¹²)₂,        —CH₂P(O)(OR¹²)₂, —OCH₂P(O)(OR¹²)₂, —C(O)OCH₂P(O)(OR¹²)₂,        —P(O)(R¹²)(OR¹²), —OP(O)(R¹²)(OR¹²), —CH₂P(O)(R¹²)(OR¹²),        —OCH₂P(O)(R¹²)(OR¹²), —C(O)OCH₂P(O)(R¹²)(OR¹²), —P(O)(N(R¹²)₂)₂,        —OP(O)(NR¹²)₂)₂, —CH₂P(O)(N(R¹²)₂)₂, —OCH₂P(O)(N(R¹²)₂)₂,        —C(O)OCH₂P(O)(N(R¹²)₂)₂, —P(O)(N(R¹²)₂)(OR¹²),        —OP(O)(N(R¹²)₂)(OR¹²), —CH₂P(O)(N(R¹²)₂)(OR¹²),        —OCH₂P(O)(N(R¹²)₂)(OR¹²), —C(O)OCH₂P(O)(N(R¹²)₂)(OR¹²),        —P(O)(R¹²)(N(R¹²)₂), —OP(O)(R¹²)(N(R¹²)₂),        —CH₂P(O)(R¹²)(N(R¹²)₂), —OCH₂P(O)(R¹²)(N(R¹²)₂),        —C(O)OCH₂P(O)(R¹²)N(R¹²)₂), —Si(R¹²)₃, —S—R¹², —S(O)R¹²,        —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl,        aryl, heteroaryl or heterocyclyl is optionally substituted with        one to four Z^(1a) groups;        each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl,        haloalkyl, hydroxyalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹²,        —C(O)R¹², —C(O)O—R¹², —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴),        —N(R¹³)₂(R¹⁴)⁺, —N(R¹²)—C(O)R¹², —N(R¹²)C(O)O(R¹²),        —N(R¹²)C(O)N(R¹³)(R¹⁴), —N(R¹²)S(O)₂(R¹²),        —N(R¹²)S(O)₂—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂O(R¹²), —OC(O)R¹²,        —OC(O)OR¹², —OC(O)—N(R¹³)(R¹⁴), —C(O)N(R¹²)—S(O)₂R¹², —Si(R¹²)₃,        —S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        each R¹² is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or        heterocyclyl,    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        R¹³ and R¹⁴ at each occurrence are each independently hydrogen,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl,        heteroaryl or heterocyclyl;    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups, or R¹³ and R¹⁴ together with the nitrogen to        which they are attached form a heterocyclyl, wherein said        heterocyclyl is optionally substituted with one to four Z^(1b)        groups;        each R¹⁵ is independently halo, —CN, —NO₂, —O—R⁷, —N(R⁸)(R⁹),        —S(O)—R⁷, —S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷,        —OC(O)O—R⁷, —OC(O)N(R¹⁰)(R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl;        and        each Z^(1b) is independently oxo, thioxo, hydroxy, halo, —NO₂,        —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl,        —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅        cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl), —O(heteroaryl),        —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl),        —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₉ haloalkyl),        —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂,        —N(C₃₋₁₅ cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂,        —N(C₃₋₁₅ cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂,        —N(heteroaryl)₂, —N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅        cycloalkyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆        alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈        haloalkyl), —N(C₁₋₉ alkyl)(aryl), —N(C₁₋₉ alkyl)(heteroaryl),        —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉ alkyl), —C(O)(C₂₋₆        alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅ cycloalkyl),        —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl), —C(O)(heteroaryl),        —C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl), —C(O)O(C₂₋₆ alkenyl),        —C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅ cycloalkyl), —C(O)O(C₁₋₈        haloalkyl), —C(O)O(aryl), —C(O)O(heteroaryl),        —C(O)O(heterocyclyl), —C(O)NH₂, —C(O)NH(C₁₋₉ alkyl),        —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl), —C(O)NH(C₃₋₁₅        cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl), —C(O)NH(aryl),        —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,        —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆        alkynyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂,        —C(O)N(aryl)₂, —C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂,        —NHC(O)(C₁₋₉ alkyl), —NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆        alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl), —NHC(O)O(C₂₋₆        alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl),        —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl),        —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl), —NHC(O)NH(C₂₋₆        alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈        haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),        —NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl), —S(C₂₋₆ alkenyl),        —S(C₂₋₆ alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₉ haloalkyl),        —S(aryl), —S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl),        —N(C₁₋₉ alkyl)(S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆        alkynyl), —S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁₋₈ haloalkyl),        —S(O)(aryl), —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉        alkyl), —S(O)₂(C₂₋₆ alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        or —S(O)₂N(C₁₋₉ alkyl)₂;    -   wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl        is optionally substituted with one to four halo, C₁₋₉ alkyl,        C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉ alkyl), —NH(C₃₋₁₅        cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl), —NH(heteroaryl),        —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅ cycloalkyl)₂,        —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅        cycloalkyl), —NHC(O)O(C haloalkyl), —NHC(O)O(aryl),        —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),        —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl);        m is 0, 1, or 2;        or a pharmaceutically acceptable salt, tautomer, stereoisomer,        mixture of stereoisomers, prodrug, or deuterated analog thereof.

In certain embodiments, the compound of Formula I is represented byFormula IA:

wherein R¹-R⁶, R¹⁵ and in are as described herein.

In certain embodiments, the compound of Formula I is represented byFormula IB:

wherein R¹-R⁶, R¹⁵ and m are as described herein.

In certain embodiments, m is 0. In certain embodiments, R² is hydrogen.

In certain embodiments, provided is a compound of Formula II:

wherein R¹, R³, R⁴, R⁵ and R⁶ are as defined herein.

In certain embodiments, provided is a compound of Formula IIA:

wherein R¹, R³, R⁴, R⁵ and R⁶ are as defined herein.

In certain embodiments, provided is a compound of Formula III:

wherein R¹, R⁴, R⁵ and R⁶ are as defined herein,W, X and Y are each independently N or C;n is 1, 2, or 3;each Z³ is independently hydrogen, oxo, halo, —NO₂, —N₃, —CN, thioxo,C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)—R¹²,—C(O)O—R¹², —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,—N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹³)(R¹⁴),—N(R¹²)S(O)₂(R¹²)⁺, —NR¹²S(O)₂N(R¹³)(R¹⁴), —NR¹²S(O)₂O(R¹²), —OC(O)R¹²,—OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂, —OP(O)(OR¹²)₂, —CH₂P(O)(OR¹²)₂,—OCH₂P(O)(OR¹²)₂, —C(O)OCH₂P(O)(OR¹²)₂, —P(O)(R¹²)(OR¹²),—OP(O)(R¹²)(OR¹²), —CH₂P(O)(R¹²)(OR¹²), OCH₂P(O)(R¹²)(OR¹²),—C(O)OCH₂P(O)(R¹²)(OR¹²), —P(O)(N(R¹²)₂)₂, —OP(O)(N(R¹²)₂)₂,—CH₂P(O)(N(R¹²)₂)₂, —OCH₂P(O)(N(R¹²)₂)₂, —C(O)OCH₂P(O)(N(R¹²)₂)₂,—P(O)(N(R¹²)₂)(OR¹²), —OP(O)(N(R¹²)₂)(OR¹²), —CH₂P(O)(N(R¹²)₂)(OR¹²),—OCH₂P(O)(N(R¹²)₂)(OR¹²), —C(O)OCH₂P(O)(N(R¹²)₂)(OR¹²),—P(O)(R¹²)(NR¹²)₂), —OP(O)(R¹²)(N(R¹²)₂), —CH₂P(O)(R¹²)(N(R¹²)₂),—OCH₂P(O)(R¹²)(N(R¹²)₂), —C(O)OCH₂P(O)(R¹²)(N(R¹²)₂), —Si(R¹²)₃,—S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);

-   -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1a) groups;        each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈        haloalkyl, C₁₋₈ hydroxyalkyl, aryl, heteroaryl, heterocyclyl,        —O—R¹², —C(O)R¹², —C(O)O—R¹², —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴),        —N(R¹³)₂(R¹⁴)⁺, —C(O)N(R¹²)—S(O)₂R¹², —N(R¹²)—C(O)R¹²,        —N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹³)(R¹⁴), —N(R¹²)S(O)₂(R¹²),        —N(R¹²)S(O)₂—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂O(R¹²), —OC(O)R¹²,        —OC(O)OR¹², —OC(O)—N(R¹³)(R¹⁴), —Si(R¹²)₃, —S—R¹², —S(O)R¹²,        —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        each R¹² is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or        heterocyclyl,    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        R¹³ and R¹⁴ at each occurrence are each independently hydrogen,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl,        heteroaryl or heterocyclyl;    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups, or R¹³ and R¹⁴ together with the nitrogen to        which they are attached form a heterocyclyl, wherein said        heterocyclyl is optionally substituted with one to four Z^(1b)        groups; and        each Z^(1b) is independently oxo, thioxo, hydroxy, halo, —NO₂,        —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl,        —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅        cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl), —O(heteroaryl),        —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl),        —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₉ haloalkyl),        —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), alkyl)₂, —N(C₃₋₁₅        cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅        cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,        —N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), alkyl)(C₂₋₆        alkenyl), alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅        cycloalkyl), alkyl)(C₁₋₈ haloalkyl), alkyl)(aryl),        alkyl)(heteroaryl), alkyl)(heterocyclyl), —C(O)(C₁₋₉ alkyl),        —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅        cycloalkyl), —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl),        —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl),        —C(O)O(C₂₋₆alkenyl), —C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅        cycloalkyl), —C(O)O(C₁₋₈ haloalkyl), —C(O)O(aryl),        —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂, —C(O)NH(C₁₋₉        alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),        —C(O)NH(C₃₋₁₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl),        —C(O)NH(aryl), —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl),        —C(O)N(C₁₋₉ alkyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆        alkenyl)₂, —C(O)N(C₂₋₆ alkynyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂,        —C(O)N(C₁₋₈ haloalkyl)₂, —C(O)N(aryl)₂, —C(O)N(heteroaryl)₂,        —C(O)N(heterocyclyl)₂, —NHC(O)(C₁₋₉ alkyl), —NHC(O)(C₂₋₆        alkenyl), —NHC(O)(C₂₋₆ alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl),        —NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),        —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆        alkenyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),        —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),        —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆        alkenyl), —NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl),        —NHC(O)NH(C₁₋₈ haloalkyl), —NHC(O)NH(aryl),        —NHC(O)NH(heteroaryl), —NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉        alkyl), —S(C₂₋₆ alkenyl), —S(C₂₋₆ alkynyl), —S(C₃₋₁₅        cycloalkyl), haloalkyl), —S(aryl), —S(heteroaryl),        —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl), —N(C₁₋₉ alkyl)(S(O)(C₁₋₉        alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉        alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆ alkynyl), —S(O)(C₃₋₁₅        cycloalkyl), —S(O)(C₁₋₈ haloalkyl), —S(O)(aryl),        —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉ alkyl),        —S(O)₂(C₂₋₆ alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        or —S(O)₂N(C₁₋₉ alkyl)₂;    -   wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl        is optionally substituted with one to four halo, C₁₋₉ alkyl,        C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉ alkyl), —NH(C₃₋₁₅        cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl), —NH(heteroaryl),        —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅ cycloalkyl)₂,        —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅        cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl),        —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),        —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl);        or a pharmaceutically acceptable salt, tautomer, stereoisomer,        mixture of stereoisomers, prodrug, or deuterated analog thereof.

In certain embodiments, provided is a compound of Formula IIIA:

wherein R¹, R⁴, R⁵ and R⁶ are as defined herein,W, X and Y are each independently N or C;n is 1, 2, or 3;each Z³ is independently hydrogen, oxo, halo, —NO₂, —N₃, —CN, thioxo,C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)—R¹²,—C(O)O—R¹², —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,—N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹³)(R¹⁴),—N(R¹²)S(O)₂(R¹²), —NR¹²S(O)₂N(R¹³)(R¹⁴), —NR¹²S(O)₂O(R¹²), —OC(O)R¹²,—OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂, —OP(O)(OR¹²)₂, —CH₂P(O)(OR¹²)₂,—OCH₂P(O)(OR¹²)₂, —C(O)OCH₂P(O)(OR¹²)₂, —P(O)(R¹²)(OR¹²),—OP(O)(R¹²)(OR¹²), —CH₂P(O)(R¹²)(OR¹²), OCH₂P(O)(R¹²)(OR¹²),—C(O)OCH₂P(O)(R¹²)(OR¹²), —P(O)(N(R¹²)₂)₂, —OP(O)(N(R¹²)₂)₂,—CH₂P(O)(N(R¹²)₂)₂, —OCH₂P(O)(N(R¹²)₂)₂, —C(O)OCH₂P(O)(N(R¹²)₂)₂,—P(O)(N(R¹²)₂)(OR¹²), —OP(O)(N(R¹²)₂)(OR¹²), —CH₂P(O)(N(R¹²)₂)(OR¹²),—OCH₂P(O)(N(R¹²)₂)(OR¹²). —C(O)OCH₂P(O)(N(R¹²)₂)(OR¹²),—P(O)(R¹²)(NR¹²)₂), —OP(O)(R¹²)(N(R¹²)₂), —CH₂P(O)(R¹²)(N(R¹²)₂),—OCH₂P(O)(R¹²)(N(R¹²)₂), —C(O)OCH₂P(O)(R¹²)(N(R¹²)₂), —Si(R¹²)₃, —S—R¹²,—S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);

-   -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1a) groups;        each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₉        haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹²,        —C(O)O—R¹², —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,        —N(R¹²)—C(O)R¹², —N(R¹²)C(O)O(R¹²), —N(R¹²)S(O)₂(R¹²),        —N(R¹²)S(O)₂—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂O(R¹²), —OC(O)R¹²,        —OC(O)OR¹², —OC(O)—N(R¹³)(R¹⁴), —Si(R¹²)₃, —S—R¹², —S(O)R¹²,        —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        each R¹² is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or        heterocyclyl,    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        R¹³ and R¹⁴ at each occurrence are each independently hydrogen,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl,        heteroaryl or heterocyclyl;    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups, or R¹³ and R¹⁴ together with the nitrogen to        which they are attached form a heterocyclyl, wherein said        heterocyclyl is optionally substituted with one to four Z^(1b)        groups; and        each Z^(1b) is independently oxo, thioxo, hydroxy, halo, —NO₂,        —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl,        —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅        cycloalkyl), haloalkyl), —O(aryl), —O(heteroaryl),        —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl),        —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₉ haloalkyl),        —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), alkyl)₂, —N(C₃₋₁₅        cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅        cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,        —N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉        alkyl)(C₂₋₆ alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉        alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈ haloalkyl),        —N(C₁₋₉ alkyl)(aryl), —N(C₁₋₉ alkyl)(heteroaryl),        alkyl)(heterocyclyl), —C(O)(C₁₋₉ alkyl), —C(O)(C₂₋₆ alkenyl),        —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅ cycloalkyl), —C(O)(C₁₋₈        haloalkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl),        —C(O)O(C₁₋₉ alkyl), —C(O)O(C₂₋₆ alkenyl), —C(O)O(C₂₋₆ alkynyl),        —C(O)O(C₃₋₁₅ cycloalkyl), —C(O)O(C₁₋₈ haloalkyl), —C(O)O(aryl),        —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂, —C(O)NH(C₁₋₉        alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),        —C(O)NH(C₃₋₁₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl),        —C(O)NH(aryl), —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl),        —C(O)N(C₁₋₉ alkyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆        alkenyl)₂, —C(O)N(C₂₋₆ alkynyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂,        —C(O)N(C₁₋₈ haloalkyl)₂, —C(O)N(aryl)₂, —C(O)N(heteroaryl)₂,        —C(O)N(heterocyclyl)₂, —NHC(O)(C₁₋₉ alkyl), —NHC(O)(C₂₋₆        alkenyl), —NHC(O)(C₂₋₆ alkynyl), —NHC(O) (C₃₋₁₅ cycloalkyl),        —NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),        —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆        alkenyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),        —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),        —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆        alkenyl), —NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl),        —NHC(O)NH(C₁₋₈ haloalkyl), —NHC(O)NH(aryl),        —NHC(O)NH(heteroaryl), —NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉        alkyl), —S(C₂₋₆ alkenyl), —S(C₂₋₆ alkynyl), —S(C₃₋₁₅        cycloalkyl), haloalkyl), —S(aryl), —S(heteroaryl),        —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl), —N(C₁₋₉ alkyl)(S(O)(C₁₋₉        alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉        alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆ alkynyl), —S(O)(C₃₋₁₅        cycloalkyl), —S(O)(C₁₋₈ haloalkyl), —S(O)(aryl),        —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉ alkyl),        —S(O)₂(C₂₋₆ alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        or —S(O)₂N(C₁₋₉ alkyl)₂;    -   wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl        is optionally substituted with one to four halo, C₁₋₉ alkyl,        C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉ alkyl), —NH(C₃₋₁₅        cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl), —NH(heteroaryl),        —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅ cycloalkyl)₂,        —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅        cycloalkyl), —NHC(O)O(C haloalkyl), —NHC(O)O(aryl),        —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),        —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl);        or a pharmaceutically acceptable salt, tautomer, stereoisomer,        mixture of stereoisomers, prodrug, or deuterated analog thereof.

In certain embodiments, provided is a compound of Formula IIIA:

wherein R¹, R⁴, R⁵ and R⁶ are as defined in claim 1,W, X and Y are each independently N or C;n is 1, 2, or 3;each Z³ is independently hydrogen, oxo, halo, —NO₂, —N₃, —CN, thioxo,C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)—R¹²,—C(O)O—R¹², —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,—N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹³)(R¹⁴),—N(R¹²)S(O)₂(R¹²), —NR¹²S(O)₂N(R¹³)(R¹⁴), —NR¹²S(O)₂O(R¹²), —OC(O)R¹²,—OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂, —OP(O)(OR¹²)₂, —CH₂P(O)(OR¹²)₂,—OCH₂P(O)(OR¹²)₂, —C(O)OCH₂P(O)(OR¹²)₂, —P(O)(R¹²)(OR¹²),—OP(O)(R¹²)(OR¹²), —CH₂P(O)(R¹²)(OR¹²), —OCH₂P(O)(R¹²)(OR¹²),—C(O)OCH₂P(O)(R¹²)(OR¹²), —P(O)(N(R¹²)₂)₂, —OP(O)(N(R¹²)₂)₂,—CH₂P(O)(N(R¹²)₂)₂, —OCH₂P(O)(N(R¹²)₂)₂, —C(O)OCH₂P(O)(N(R¹²)₂)₂,—P(O)(N(R¹²)₂)(OR¹²), —OP(O)(N(R¹²)₂)(OR¹²), —CH₂P(O)(N(R¹²)₂)(OR¹²),—OCH₂P(O)(N(R¹²)₂)(OR¹²), —C(O)OCH₂P(O)(N(R¹²)₂)(OR¹²),—P(NR¹²)(N(R¹²)₂), —OP(O)(R¹²)(N(R¹²)₂), —CH₂P(O)(R¹²)(N(R¹²)₂),—OCH₂P(O)(R¹²)(N(R¹²)₂), —C(O)OCH₂P(O)(R¹²)(N(R¹²)₂). —Si(R¹²)₃, —S—R¹²,—S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);

-   -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1a) groups;        each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈        haloalkyl, C₁₋₈ hydroxyalkyl, aryl, heteroaryl, heterocyclyl,        —O—R¹², —C(O)R¹², —C(O)O—R¹², —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴),        —N(R¹³)₂(R¹⁴)⁺, —N(R¹²)—C(O)R¹², —N(R¹²)C(O)O(R¹²),        —N(R¹²)C(O)N(R¹³)(R¹⁴), —N(R¹²)S(O)₂(R¹²),        —N(R¹²)S(O)₂—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂O(R¹²), —OC(O)R¹²,        —OC(O)OR¹², —OC(O)—N(R¹³)(R¹⁴), —Si(R¹²)₃, —S—R¹², —S(O)R¹²,        —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        each R¹² is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or        heterocyclyl,    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        R¹³ and R¹⁴ at each occurrence are each independently hydrogen,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl,        heteroaryl or heterocyclyl;    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups, or R¹³ and R¹⁴ together with the nitrogen to        which they are attached form a heterocyclyl, wherein said        heterocyclyl is optionally substituted with one to four Z^(1b)        groups; and        each Z^(1b) is independently oxo, thioxo, hydroxy, halo, —NO₂,        —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl,        —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅        cycloalkyl), haloalkyl), —O(aryl), —O(heteroaryl),        —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl),        —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₉ haloalkyl),        —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), alkyl)₂, —N(C₃₋₁₅        cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅        cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,        —N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), alkyl)(C₂₋₆        alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅        cycloalkyl), alkyl)(C₁₋₈ haloalkyl), alkyl)(aryl),        alkyl)(heteroaryl), alkyl)(heterocyclyl), —C(O)(C₁₋₉ alkyl),        —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅        cycloalkyl), —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl),        —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl),        —C(O)O(C₂₋₆ alkenyl), —C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅        cycloalkyl), —C(O)O(C₁₋₈ haloalkyl), —C(O)O(aryl),        —C(O)O(heteroaryl), —C(O)O(heterocyclyl),        —C(O)NH₂₉—C(O)NH(C₁₋₉alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆        alkynyl), —C(O)NH(C₃₋₁₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl),        —C(O)NH(aryl), —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl),        —C(O)N(C₁₋₉ alkyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆        alkenyl)₂, —C(O)N(C₂₋₆ alkynyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂,        —C(O)N(C₁₋₈ haloalkyl)₂, —C(O)N(aryl)₂, —C(O)N(heteroaryl)₂,        —C(O)N(heterocyclyl)₂, —NHC(O)(C₁₋₉ alkyl), —NHC(O)(C₂₋₆        alkenyl), —NHC(O)(C₂₋₆ alkynyl), —NHC(O) (C₃₋₁₅ cycloalkyl),        —NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),        —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆        alkenyl), —NHC(O)O(C₂-6 alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),        —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),        —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆        alkenyl), —NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl),        —NHC(O)NH(C₁₋₈ haloalkyl), —NHC(O)NH(aryl),        —NHC(O)NH(heteroaryl), —NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉        alkyl), —S(C₂₋₆ alkenyl), —S(C₂₋₆ alkynyl), —S(C₃₋₁₅        cycloalkyl), —S(C₁₋₈ haloalkyl), —S(aryl), —S(heteroaryl),        —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl), —N(C₁₋₉ alkyl)(S(O)(C₁₋₉        alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉        alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆ alkynyl), —S(O)(C₃₋₁₅        cycloalkyl), —S(O)(C₁₋₈ haloalkyl), —S(O)(aryl),        —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉ alkyl),        —S(O)₂(C₂₋₆ alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        or —S(O)₂N(C₁₋₉ alkyl)₂;    -   wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl        is optionally substituted with one to four halo, C₁₋₉ alkyl,        C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉ alkyl), —NH(C₃₋₁₅        cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl), —NH(heteroaryl),        —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅ cycloalkyl)₂,        —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅        cycloalkyl), —NHC(O)O(C haloalkyl), —NHC(O)O(aryl),        —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),        —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl);        or a pharmaceutically acceptable salt, tautomer, stereoisomer,        mixture of stereoisomers, prodrug, or deuterated analog thereof.

In certain embodiments, W is N, X is N—Z³, and Y is C—Z³. In certainembodiments, W is C—Z³, X is N—Z³, and Y is C—Z³.

In certain embodiments, the compound of Formula I is represented byFormula IV:

wherein R¹, R³, R⁵, R⁶ and Z⁴ are as defined herein, q is 0, 1, 2, 3 or4, ring A is a 5- or 6-membered cycloalkyl, heterocyclyl or heteroarylring, and ring B is a 6-membered cycloalkyl, heterocyclyl or heteroarylring, provided that at least one heteroatom is present in ring A or ringB such that R⁴ is an optionally substituted bicyclic heterocyclyl oroptionally substituted bicyclic heteroaryl. In the above, the wavy lineindicates the point of attachment to the remainder of the molecule,where the attachment can through either ring (i.e., ring A or ring B) ofthe optionally substituted bicyclic heterocyclyl or optionallysubstituted bicyclic heteroaryl. In some embodiments, ring A and/or ringB comprisies an oxo (═O).

In certain embodiments, provided is a compound of Formula IVA:

wherein R¹, R³, R⁵, R⁶, Z⁴, q, ring A and ring B are as defined herein.

In certain embodiments, provided is a compound of Formula V:

wherein W, X, Y, R¹, R⁵, R⁶, Z³, Z⁴, q, n, ring A and ring B are asdefined herein.

In certain embodiments, provided is a compound of Formula VA:

wherein W, X, Y, R¹, R⁵, R⁶, Z³, Z⁴, q, n, ring A and ring B are asdefined herein.

In certain embodiments, the compound of Formula I is represented byFormula VI:

wherein R¹, R⁵, R⁶, Z³, Z⁴, q, n, ring A and ring B are as definedherein and Z⁹ is hydrogen, halo, —CN, or —O—R¹².

In certain embodiments, the compound of Formula I is represented byFormula VIA:

wherein R¹, R⁵, R⁶, Z³, Z⁴, q, n, ring A and ring B are as definedherein and Z⁹ is hydrogen, halo, —CN, or —O—R¹².

In certain embodiments, the compound of Formula I is represented byFormula VII:

wherein R¹, R⁵, R⁶, Z³, Z⁴, q, n, ring A and ring B are as definedherein.

In certain embodiments, the compound of Formula I is represented byFormula VIIA:

wherein R¹, R⁵, R⁶, Z³, Z⁴, q, n, ring A and ring B are as definedherein.

In certain embodiments, the compound of Formula I is represented byFormula VIII or IX:

wherein Z³, R¹, R⁴, R⁵ and R⁶ are as defined herein and Z⁹ is hydrogen,halo, —CN, or —O—R¹².

In certain embodiments, the compound of Formula I is represented byFormula VIIIA or IXA:

wherein Z³, R¹, R⁴, R⁵ and R⁶ are as defined herein and Z⁹ is hydrogen,halo, —CN, or —O—R¹².

In certain embodiments, the compound of Formula I is represented byFormula X or XI:

wherein Z³, R¹, R⁴, R⁵ and R⁶ are as defined herein.

In certain embodiments, the compound of Formula I is represented byFormula XA or XIA:

wherein Z³, R¹, R⁴, R⁵ and R⁶ are as defined herein.

In certain embodiments, R⁶ is hydrogen.

In certain embodiments, Z³ is hydrogen, C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl,heterocyclyl, aryl, or heteroaryl;

wherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, orheteroaryl, may be optionally substituted with one to four substituentsindependently selected from the group consisting of —CN, halo, —O—R¹²,—C(O)R¹², —OC(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴),—N(R¹³)₂(R¹⁴)⁺, —S(O)₂—R¹², —Si(R¹²)₃, C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl,aryl, heterocyclyl, and heteroaryl; and

-   -   wherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl,        or heteroaryl may be optionally substituted with one to three        substituents independently selected from the group consisting of        halo, —O(C₁₋₉ alkyl), —C(O)N(C₁₋₉ alkyl)₂, C₁₋₉ alkyl, and        heterocyclyl.

In certain embodiments, Z³ is hydrogen, C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl,heterocyclyl, aryl, or heteroaryl;

-   -   wherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, aryl, or        heterocyclyl, may be optionally substituted with one to four        substituents independently selected from the group consisting of        —CN, halo, —O—R¹², —C(O)—R¹², —OC(O)—R¹², —C(O)O—R¹²,        —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, —S(O)₂—R¹²,        —Si(R¹²)₃, C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and        heteroaryl; and    -   wherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, heterocyclyl, or aryl        may be optionally substituted with one to three substituents        independently selected from the group consisting of halo,        —O(C₁₋₉ alkyl), —C(O)N(C₁₋₉ alkyl)₂, C₁₋₉ alkyl, and        heterocyclyl.

In certain embodiments, Z³ is hydrogen or C₁₋₉ alkyl;

-   -   wherein said C₁₋₉ alkyl may be optionally substituted with one        to four substituents independently selected from the group        consisting of —CN, halo, —O—R¹², —C(O)—R¹², —OC(O)—R¹²,        —C(O)O—R¹², —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,        —S(O)₂—R¹², —Si(R¹²)₃, C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, aryl,        heterocyclyl, and heteroaryl; and        -   wherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, heterocyclyl, or            aryl may be optionally substituted with one to three            substituents independently selected from the group            consisting of halo, —O(C₁₋₉ alkyl), —C(O)N(C₁₋₉ alkyl)₂,            C₁₋₉ alkyl, and heterocyclyl.

In certain embodiments, Z³ is hydrogen or C₁₋₉ alkyl optionallysubstituted with one to four substituents independently selected fromthe group consisting of —CN, halo, —O—R¹², —C(O)O—R¹², —OC(O)—R¹²,—N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, C₁₋₉ alkyl, heterocyclyl, and heteroaryl.

In certain embodiments, Z³ is C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, orheteroaryl;

-   -   wherein said C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, or        heteroaryl, may be optionally substituted with one to four        substituents independently selected from the group consisting of        —CN, halo, —O—R¹², —C(O)—R¹², —OC(O)—R¹², —C(O)O—R¹²,        —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, —S(O)₂—R¹²,        —Si(R¹²)₃, C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and        heteroaryl; and        -   wherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, aryl,            heterocyclyl, or heteroaryl may be optionally substituted            with one to three substituents independently selected from            the group consisting of halo, —O(C₁₋₉ alkyl), —C(O)N(C₁₋₉            alkyl)₂, C₁₋₉ alkyl, and heterocyclyl.

In certain embodiments, Z³ is C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, orheteroaryl;

-   -   wherein said C₃₋₁₅ cycloalkyl, heterocyclyl, or aryl may be        optionally substituted with one to four substituents        independently selected from the group consisting of —CN, halo,        —O—R¹², —C(O)—R¹², —OC(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹³)(R¹⁴),        —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, —S(O)₂—R¹², —Si(R¹²)₃, C₁₋₉ alkyl,        C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl; and        -   wherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, heterocyclyl, or            aryl may be optionally substituted with one to three            substituents independently selected from the group            consisting of halo, —O(C₁₋₉ alkyl), —C(O)N(C₁₋₉ alkyl)₂,            C₁₋₉ alkyl, and heterocyclyl.

In certain embodiments, Z³ is hydrogen or C₁₋₉ alkyl optionallysubstituted with one to four substituents independently selected fromthe group consisting of —CN, halo, —O—R¹², —C(O)O—R¹², —OC(O)—R¹²,—N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, —C(O)N(R¹²)—S(O)₂R¹², C₁₋₉ alkyl,heterocyclyl, aryl, and heteroaryl.

In certain embodiments, Z³ is hydrogen or C₁₋₉ alkyl optionallysubstituted with one to four substituents independently selected fromthe group consisting of —CN, halo, —O—R¹², —C(O)O—R¹², —OC(O)—R¹²,—N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, C₁₋₉ alkyl, heterocyclyl, and heteroaryl.

In certain embodiments, Z³ is C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, orheteroaryl; and said C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, or heteroarylmay be optionally substituted with one to four substituentsindependently selected from the group consisting of —CN, halo, —O—R¹²,—C(O)—R¹², —C(O)O—R¹², —OC(O)—R¹², —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, C₁₋₉alkyl, C₁₋₈ haloalkyl, C₁₋₈ hydroxyalkyl, C₃₋₁₅ cycloalkyl,heterocyclyl, and heteroaryl.

In certain embodiments, Z³ is C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, orheteroaryl; and said C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, or heteroarylmay be optionally substituted with one to four substituentsindependently selected from the group consisting of —CN, halo, —O—R¹²,—C(O)O—R¹², —OC(O)—R¹², —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, C₁₋₉ alkyl,heterocyclyl, and heteroaryl.

In certain embodiments, Z³ is hydrogen, C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl,heterocyclyl, aryl, or heteroaryl;

-   -   wherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, or heterocyclyl may        be optionally substituted with one to four substituents        independently selected from the group consisting of oxo, —CN,        halo, —O—R¹², —C(O)—R¹², —C(O)O—R¹², —OC(O)—R¹²,        —C(O)—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂(R¹²), —N(R¹³)(R¹⁴),        —N(R¹³)₂(R¹⁴)⁺, —C(O)N(R¹²)—S(O)₂R¹², C₁₋₉ alkyl, C₁₋₈        haloalkyl, C₁₋₈ hydroxyalkyl, C₃₋₁₅ cycloalkyl, aryl,        heterocyclyl, and heteroaryl;        Z⁹ is hydrogen;        R¹ is C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, or        heteroaryl;    -   wherein said C₁₋₉ alkyl, heterocyclyl, aryl, or heteroaryl may        be optionally substituted with one to three substituents        independently selected the group consisting of halo, —CN,        —O—R¹², —S(O)₂R¹², C₁₋₉ alkyl, C₁₋₉ haloalkyl, heterocyclyl, and        aryl, wherein said C₃₋₁₅ cycloalkyl may be optionally        substituted with one to four substituents independently selected        the group consisting of C₁₋₉ alkyl, and C₁₋₉ haloalkyl;        R⁴ is heterocyclyl or heteroaryl;    -   wherein said heterocyclyl or heteroaryl is optionally        substituted with one to three substituents independently        selected from the group consisting of —CN, halo, —O—R¹²,        —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl, C₁₋₉ haloalkyl, and        heterocyclyl;        R⁵ is —CN, halo, —O—R⁷ or —S(O)₂R⁷;        R⁶ is hydrogen;        each R⁷ is independently hydrogen or C₁₋₉ alkyl;    -   wherein said C₁₋₉ alkyl may be optionally substituted with one        to three substituents independently selected from the group        consisting of hydroxyl, halo, —O(C₁₋₉ alkyl) and aryl;        each R¹² is independently hydrogen, C₁₋₉ alkyl or heterocyclyl;    -   wherein said C₁₋₉ alkyl may be optionally substituted with one        to three substituents independently selected from the group        consisting of hydroxyl, halo, —O(C₁₋₉ alkyl) and aryl; and        each R¹³ and R¹⁴ is independently hydrogen or C₁₋₉ alkyl;    -   wherein said C₁₋₉ alkyl may be optionally substituted with one        to three substituents independently selected from the group        consisting of hydroxyl, halo, —O(C₁₋₉ alkyl) and aryl;        or a pharmaceutically acceptable salt, tautomer, stereoisomer,        mixture of stereoisomers, or deuterated analog thereof.

In certain embodiments, Z³ is hydrogen, C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl,heterocyclyl, aryl, or heteroaryl;

-   -   wherein said C₁₋₉ alkyl, or heterocyclyl may be optionally        substituted with one to four substituents independently selected        from the group consisting of —CN, halo, —O—R¹², —C(O)O—R¹²,        —OC(O)—R¹², —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, C₁₋₉ alkyl,        heterocyclyl, and heteroaryl;        R¹ is C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, or        heteroaryl;    -   wherein said C₁₋₉ alkyl, heterocyclyl, aryl, or heteroaryl may        be optionally substituted with one to three substituents        independently selected the group consisting of halo, —CN,        —O—R¹², C₁₋₉ alkyl and aryl;        R⁴ is heterocyclyl or heteroaryl;    -   wherein said heterocyclyl or heteroaryl is optionally        substituted with one to three substituents independently        selected from the group consisting of —CN, halo, —O—R¹²,        —C(O)—R¹², C₁₋₉ alkyl, C₁₋₉ haloalkyl, and heterocyclyl;        R⁵ is —CN, halo, or —O—R⁷;        R⁶ is hydrogen;        each R⁷ is independently hydrogen or C₁₋₉ alkyl;    -   wherein said C₁₋₉ alkyl may be optionally substituted with one        to three substituents independently selected from the group        consisting of hydroxyl, halo, —O(C₁₋₉ alkyl) and aryl;        each R¹² is independently hydrogen or C₁₋₉ alkyl;    -   wherein said C₁₋₉ alkyl may be optionally substituted with one        to three substituents independently selected from the group        consisting of hydroxyl, halo, —O(C₁₋₉ alkyl) and aryl; and        each R¹³ and R¹⁴ is independently hydrogen or C₁₋₉ alkyl;    -   wherein said C₁₋₉ alkyl may be optionally substituted with one        to three substituents independently selected from the group        consisting of hydroxyl, halo, —O(C₁₋₉ alkyl) and aryl;        or a pharmaceutically acceptable salt, tautomer, stereoisomer,        mixture of stereoisomers, prodrug, or deuterated analog thereof.

In certain embodiments, Z³ is hydrogen, C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl,heterocyclyl, aryl, or heteroaryl;

-   -   wherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, or heterocyclyl may        be optionally substituted with one to four substituents        independently selected from the group consisting of oxo, —CN,        halo, —O—R¹², —C(O)—R¹², —C(O)O—R¹², —OC(O)—R¹²,        —C(O)—N(R¹³)(R¹⁴), —N(R¹²)S( )₂(R¹²), —N(R¹³)(R¹⁴),        —N(R¹³)₂(R¹⁴)⁺, C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, aryl,        heterocyclyl, and heteroaryl;        -   wherein said C₁₋₉ alkyl may be optionally substituted with            one to four substituents independently selected from the            group consisting of halo and hydroxyl.            R¹ is C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, or            heteroaryl;    -   wherein said C₁₋₉ alkyl, heterocyclyl, aryl, or heteroaryl may        be optionally substituted with one to three substituents        independently selected the group consisting of halo, —CN,        —O—R¹², C₁₋₉ alkyl and aryl;        R⁴ is heterocyclyl or heteroaryl;    -   wherein said heterocyclyl or heteroaryl is optionally        substituted with one to three substituents independently        selected from the group consisting of —CN, halo, —O—R¹²,        —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl, C₁₋₉ haloalkyl, and        heterocyclyl;        R⁵ is —CN, halo, —O—R⁷ or —S(O)₂R⁷;        R⁶ is hydrogen;        each R⁷ is independently hydrogen or C₁₋₉ alkyl;    -   wherein said C₁₋₉ alkyl may be optionally substituted with one        to three substituents independently selected from the group        consisting of hydroxyl, halo, —O(C₁₋₉ alkyl) and aryl;        each R¹² is independently hydrogen, C₁₋₉ alkyl or heterocyclyl;    -   wherein said C₁₋₉ alkyl may be optionally substituted with one        to three substituents independently selected from the group        consisting of hydroxyl, halo, —O(C₁₋₉ alkyl) and aryl; and        each R¹³ and R¹⁴ is independently hydrogen or C₁₋₉ alkyl;    -   wherein said C₁₋₉ alkyl may be optionally substituted with one        to three substituents independently selected from the group        consisting of hydroxyl, halo, —O(C₁₋₉ alkyl) and aryl;        or a pharmaceutically acceptable salt, tautomer, stereoisomer,        mixture of stereoisomers, or deuterated analog thereof.

In certain embodiments, Z³ is C₃₋₁₅ cycloalkyl optionally substitutedwith one to four substituents independently selected from the groupconsisting of —CN, halo, —C(O)—R¹², —OC(O)—R¹², —C(O)N(R¹³)(R¹⁴), C₁₋₉alkyl, C₁₋₈ haloalkyl, C₁₋₈ hydroxyalkyl, C₃₋₁₅ cycloalkyl, andheteroaryl.

In certain embodiments, Z³ is heterocyclyl optionally substituted withone to four substituents independently selected from the groupconsisting of —O—R¹², —C(O)O—R¹², C₁₋₉ alkyl, C₁₋₈ haloalkyl, C₁₋₈hydroxyalkyl, and heterocyclyl.

In certain embodiments, R¹ is C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl,heterocyclyl, aryl, or heteroaryl; and said C₁₋₉ alkyl, C₃₋₁₅cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionallysubstituted with one to four substituents independently selected thegroup consisting of halo, —CN, —O—R¹², C₁₋₉ alkyl, and aryl.

In certain embodiments, R¹ is —O—R⁷, C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl,heterocyclyl, aryl, or heteroaryl; and said C₁₋₉ alkyl, C₃₋₁₅cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionallysubstituted with one to four substituents independently selected thegroup consisting of halo, —CN, —O—R¹², —S(O)₂R¹², C₁₋₉ alkyl, C₁₋₉haloalkyl, C₃₋₁₅ cycloalkyl, heterocyclyl, and aryl, wherein said C₃₋₁₅cycloalkyl may be optionally substituted with one to four substituentsindependently selected the group consisting of C₁₋₉ alkyl, and C₁₋₉haloalkyl.

In certain embodiments, R¹ is —O—R⁷, C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl,heterocyclyl, aryl, or heteroaryl; and said C₁₋₉ alkyl, C₃₋₁₅cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionallysubstituted with one to four substituents independently selected thegroup consisting of halo, —CN, —O—R¹², C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, andaryl. In certain embodiments, R¹ is C₁₋₉ alkyl, optionally substitutedwith one to three substituents independently selected the groupconsisting of halo, —CN, —O—R¹², —S(O)₂R¹², C₃₋₁₅ cycloalkyl,heterocyclyl, and aryl, wherein said C₃₋₁₅ cycloalkyl or heterocyclylmay be optionally substituted with one to four substituentsindependently selected the group consisting of C₁₋₉ alkyl, and C₁₋₉haloalkyl.

In certain embodiments, R¹ is C₁₋₉ alkyl, optionally substituted withone to three substituents independently selected the group consisting ofhalo, —CN, —O—R¹², C₁₋₉ alkyl, and aryl.

In certain embodiments, R¹ is C₃₋₁₅ cycloalkyl, heterocyclyl, orheteroaryl;

-   -   wherein said C₃₋₁₅ cycloalkyl, heterocyclyl, or heteroaryl may        be optionally substituted with one to three substituents        independently selected from the group consisting of —CN, halo,        —O—R¹², —N(R¹³)(R¹⁴), —NH—C(O)O—R¹², —S(O)₂—R¹², —Si(R¹²)₃, C₁₋₉        alkyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, and heteroaryl; and        -   wherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, aryl, or            heteroaryl may be optionally substituted with one to three            substituents independently selected from the group            consisting of —CN, halo, —O—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl,            C₃₋₁₅ cycloalkyl, and aryl.

In certain embodiments, R¹ is C₃₋₁₅ cycloalkyl, heterocyclyl orheteroaryl, wherein said C₃₋₁₅ cycloalkyl, heterocyclyl or heteroaryl isoptionally substituted with one to three substituents independentlyselected the group consisting of halo, —CN, —O—R¹², C₁₋₉ alkyl, andaryl.

In certain embodiments, R¹ is R¹ is heterocyclyl or heteroaryl, whereinsaid heterocyclyl or heteroaryl is optionally substituted with one tothree substituents independently selected the group consisting of halo,and C₁₋₉ alkyl.

In certain embodiments, R¹ is aryl;

-   -   wherein said aryl may be optionally substituted with one to        three substituents independently selected from the group        consisting of —CN, halo, —O—R¹², —N(R¹³)(R¹⁴), —NH—C(O)O—R¹²,        —S(O)₂—R¹², —Si(R¹²)₃, C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl,        heterocyclyl, aryl, and heteroaryl; and        -   wherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, aryl, or            heteroaryl may be optionally substituted with one to three            substituents independently selected from the group            consisting of —CN, halo, —O—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl,            C₃₋₁₅ cycloalkyl, and aryl.

In certain embodiments, R¹ is aryl, optionally substituted with one tothree substituents independently selected the group consisting of halo,—CN, —O—R⁷, C₁₋₉ alkyl, and aryl.

In certain embodiments, R¹ is aryl, optionally substituted with one tothree substituents independently selected the group consisting of halo,—O—R⁷, and C₁₋₉ alkyl.

In one embodiment, R¹ is (1S,3S,5S,7S)-adamantan-2-yl,(R)-1-phenylethyl, (R)-1-phenylpropyl,(R)-1-phenylpropyl-1,2,2,3,3,3-d6, (R)-1-phenylpropyl-2,2,3,3,3-d5,(R)-2-cyano-1-phenylethyl, (R)-2-hydroxy-1-phenylethyl,(R)-2-hydroxy-2-methyl-1-phenylpropyl, (R)-2-methoxy-1-phenylethyl,(R)-3-cyano-1-phenylpropyl, (R)-3-fluoro-1-phenylpropyl,(R)-3-hydroxy-1-phenylpropyl, (S)-1-phenylpropyl-2,2,3,3,3-d5,(S)-2-cyano-1-phenylethyl, (S)-2-hydroxy-1-phenylethyl,(S)-2-hydroxy-2-methyl-1-phenylpropyl, (S)-3-cyano-1-phenylpropyl,(S)-3-hydroxy-1-phenylpropyl, 1-phenylpropyl-2,2,3,3,3-d5,2-cyano-1-phenylethyl, 3,3-dimethyltetrahydro-2H-pyran-4-yl,3,4-dichloro-2-fluorophenyl, 3,4-difluorophenyl,3-chloro-2,6-difluorophenyl, 3-chloro-2-fluorophenyl,3-chloro-2-methoxyphenyl, 3-chloro-4-fluorophenyl,3-chloro-4-methoxyphenyl, 3-chlorophenyl, 3-cyano-1-phenylpropyl,5,6-difluoropyridin-3-yl, 5-chloro-6-fluoropyridin-3-yl,5-chloropyridin-3-yl, cycloheptyl, cyclohexyl, neopentyl,neopentyl-1,1-d2, (1-(difluoromethyl)cyclopropyl)methyl,(1-methylcyclobutyl)methyl, (1R,5S)-bicyclo[3.1.0]hexan-6-yl,(1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl,(R)-2,2-dimethyltetrahydrofuran-3-yl, (R)-3,3-dimethylbutan-2-yl,(R)-3,3-dimethyltetrahydro-2H-pyran-4-yl, (R)-cyclopropyl(phenyl)methyl,(S)-2,2-dimethyltetrahydrofuran-3-yl,(S)-3,3-dimethyltetrahydro-2H-pyran-4-yl, 2,2-dimethylpropyl-1,1-d2,2,2-dimethyltetrahydrofuran-3-yl, 2-cyano-2-methylpropyl,2-methyl-2-phenylpropyl, 3-chloro-2,2-dimethylpropyl,3-cyano-2,2-dimethylpropyl, 3-hydroxy-2,2-dimethylpropyl, tert-butoxy,or tetrahydro-2H-pyran-4-yl.

In one embodiment, R¹ is (1S,3S,5S,7S)-adamantan-2-yl,(R)-1-phenylethyl, (R)-1-phenylpropyl,(R)-1-phenylpropyl-1,2,2,3,3,3-d6, (R)-1-phenylpropyl-2,2,3,3,3-d5,(R)-2-cyano-1-phenylethyl, (R)-2-hydroxy-1-phenylethyl,(R)-2-hydroxy-2-methyl-1-phenylpropyl, (R)-2-methoxy-1-phenylethyl,(R)-3-cyano-1-phenylpropyl, (R)-3-fluoro-1-phenylpropyl,(R)-3-hydroxy-1-phenylpropyl, (S)-1-phenylpropyl-2,2,3,3,3-d5,(S)-2-cyano-1-phenylethyl, (S)-2-hydroxy-1-phenylethyl,(S)-2-hydroxy-2-methyl-1-phenylpropyl, (S)-3-cyano-1-phenylpropyl,(S)-3-hydroxy-1-phenylpropyl, 1-phenylpropyl-2,2,3,3,3-d5,2-cyano-1-phenylethyl, 3,3-dimethyltetrahydro-2H-pyran-4-yl,3,4-dichloro-2-fluorophenyl, 3,4-difluorophenyl,3-chloro-2,6-difluorophenyl, 3-chloro-2-fluorophenyl,3-chloro-2-methoxyphenyl, 3-chloro-4-fluorophenyl,3-chloro-4-methoxyphenyl, 3-chlorophenyl, 3-cyano-1-phenylpropyl,5,6-difluoropyridin-3-yl, 5-chloro-6-fluoropyridin-3-yl,5-chloropyridin-3-y, cycloheptyl, cyclohexyl, neopentyl,neopentyl-1,1-d2, or tetrahydro-2H-pyran-4-yl.

In another embodiment, R¹ is (R)-1-phenylethyl, (R)-1-phenylpropyl,3,4-dichloro-2-fluorophenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 5,6-difluoropyridin-3-yl, or neopentyl.

In one embodiment, R² is hydrogen. In one embodiment, R² is C₁₋₆ alkyl.In one embodiment, R² is methyl.

In one embodiment, R¹ and R² together with the nitrogen atom to whichthey are attached form a heterocyclyl or heterocyclyl. In certainembodiments, R¹ and R² together with the nitrogen to which they areattached to form a heterocyclyl or heteroaryl, wherein said heterocyclylmay be optionally substituted with one to three C₁₋₉ alkyl. In certainembodiments, R¹ and R² together with the nitrogen atom to which they areattached form an optionally substituted pyrazolyl. In certainembodiments, R¹ and R² together with the nitrogen atom to which they areattached form 3,3-dimethylpiperidin-1-yl.

In one embodiment, R³ is heterocyclyl or heteroaryl, wherein eachheterocyclyl or heteroaryl is optionally substituted with one or moresubstituents (i.e., Z³) selected from the group consisting of(1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl,(1R,5S,6s)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl,(1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl, (3-hydroxyoxetan-3-yl)methyl,(R)-1,1,1-trifluoropropan-2-yl, (R)-1-ethylpyrrolidin-3-yl,(R)-pyrrolidin-3-yl, (S)-1-fluoropropan-2-yl,1-((benzyloxy)carbonyl)piperid-4-yl,1-((benzyloxy)carbonyl)pyrrolidin-4-yl,1-((tert-butyloxy)carbonyl)methyl,1-((tert-butyloxy)carbonyl)piperid-4-yl, oxetan-3-yl,1-(oxetan-3-yl)piperidin-4-yl, 1-(tert-butyl)piperidin-4-yl,1,1-difluoro-2-hydroxyethyl, 1-ethylpiperidin-4-yl,1-propylpiperidin-4-yl, 2-(2-hydroxyethoxy)ethyl,2-(2-methoxyethoxy)ethyl, 2-(diethyl(methyl)ammonio)ethyl,2-(dimethylamino)ethyl, 2-(piperidin-1-yl)ethyl, 2,2,2-trifluoroethyl,2,2,6,6-tetramethylpiperidin-4-yl, 2-aminoethyl, 2-fluoroethyl,2-hydroxyethyl, 2-methoxyethyl, 2-morpholinoethyl,3-(dimethylamino)propyl, 3-(pyrrolidin-1-yl)propyl, carboxymethyl,cyanomethyl, cyclopentyl, cyclopropyl, hydrogen, isopropyl, methyl,oxetan-3-yl, phenyl, piperidin-4-yl, pyridin-2-ylmethyl, pyridin-3-yl,(1R,2S)-2-fluorocyclopropyl, [1,1′-bi(cyclopropan)]-1-yl,1-(difluoromethyl)cyclopropyl, 1-(fluoromethyl)cyclopropyl,1-(hydroxymethyl)cyclopropyl, 1-(morpholine-4-carbonyl)cycloprop-1-yl,1-(pyridin-4-yl)cyclopropyl, 1-(pyrrolidine-1-carbonyl)cycloprop-1-yl,1-(trifluoromethyl)cyclopropyl, 1,1,1-trifluoro-2-methylpropan-2-yl,1,1-difluoro-2-methylpropan-2-yl, 1-carbamoylcyclobut-1-yl,1-carbamoylcycloprop-1-yl, 1-carboxycyclopropyl, 1-cyanocyclobutyl,1-cyanocyclopropyl, 1-fluoro-2-methylpropan-2-yl, 1-methylcyclopropyl,1-N,N-dimethylcarbamoylcycloprop-1-yl, 2-(methylsulfonamido)-2-oxoethyl,2,2-difluoroethyl, 2,6-difluorobenzyl, 3-(hydroxymethyl)oxetan-3-yl,3-(trifluoromethyl)oxetan-3-yl, 3,3-difluoro-1-(carboxy)cyclobut-1-yl,3,3-difluorocyclobutyl, bicyclo[1.1.1]pentan-1-yl, chloro, cyano,fluoro, iodo, or tert-butyl.

In one embodiment, R³ is heterocyclyl or heteroaryl, wherein eachheterocyclyl or heteroaryl is optionally substituted with one or moresubstituents (i.e., Z³) selected from the group consisting of(1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl,(1R,5S,6s)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl,(1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl, (3-hydroxyoxetan-3-yl)methyl,(R)-1,1,1-trifluoropropan-2-yl, (R)-1-ethylpyrrolidin-3-yl,(R)-pyrrolidin-3-yl, (S)-1-fluoropropan-2-yl,1-((benzyloxy)carbonyl)piperid-4-yl,1-((benzyloxy)carbonyl)pyrrolidin-4-yl,1-((tert-butyloxy)carbonyl)methyl,1-((tert-butyloxy)carbonyl)piperid-4-yl, oxetan-3-yl,1-(oxetan-3-yl)piperidin-4-yl, 1-(tert-butyl)piperidin-4-yl,1,1-difluoro-2-hydroxyethyl, 1-ethylpiperidin-4-yl,1-propylpiperidin-4-yl, 2-(2-hydroxyethoxy)ethyl,2-(2-methoxyethoxy)ethyl, 2-(diethyl(methyl)ammonio)ethyl,2-(dimethylamino)ethyl, 2-(piperidin-1-yl)ethyl, 2,2,2-trifluoroethyl,2,2,6,6-tetramethylpiperidin-4-yl, 2-aminoethyl, 2-fluoroethyl,2-hydroxyethyl, 2-methoxyethyl, 2-morpholinoethyl,3-(dimethylamino)propyl, 3-(pyrrolidin-1-yl)propyl, carboxymethyl,cyanomethyl, cyclopentyl, cyclopropyl, hydrogen, isopropyl, methyl,oxetan-3-yl, phenyl, phenyl, piperidin-4-yl, pyridin-2-ylmethyl,pyridin-3-yl, or tert-butyl.

In another embodiment, R³ is heterocyclyl or heteroaryl, wherein eachheterocyclyl or heteroaryl is optionally substituted with one or moresubstituents (i.e., Z³) selected from the group consisting of hydrogen,isopropyl, methyl, oxetan-3-yl, 1-(tert-butyl)piperidin-4-yl,1-ethylpiperidin-4-yl, cyclopropyl, 1-(trifluoromethyl)cyclopropyl,1-(difluoromethyl)cyclopropyl, 1-(fluoromethyl)cyclopropyl,1-cyanocyclopropyl, or piperidin-4-yl.

In another embodiment, R³ is heterocyclyl or heteroaryl, wherein eachheterocyclyl or heteroaryl is optionally substituted with one or moresubstituents (i.e., Z³) selected from the group consisting of hydrogen,isopropyl, methyl, oxetan-3-yl, 1-(tert-butyl)piperidin-4-yl,1-ethylpiperidin-4-yl, cyclopropyl, or piperidin-4-yl.

In one embodiment, R³ is triazolyl, pyrazolyl, isoxazolyl, isoxazolyl,oxazolyl, pyrazinyl, pyridinyl, pyrimidinyl, imidazolyl, thiadiazolyl,tetrazolyl, or oxadiazolyl, wherein each is optionally substituted byone or more Z³ groups as described herein. In one embodiment, R³ isoptionally substituted triazole (e.g., 1H-1,2,3-triazolyl).

In certain embodiments, R³ is triazole substituted with one or moresubstituents selected from the group consisting of1-(benzyloxycarbonyl)piperidin-4-yl, 1-(tert-butyl)piperidin-4-yl,1-ethylpiperidin-4-yl, cyclopropyl, isopropyl, methyl, andpiperidin-4-yl.

In one embodiment, R⁴ is heterocyclyl or heteroaryl; and saidheterocyclyl or heteroaryl is optionally substituted with one to threesubstituents independently selected from the group consisting of —CN,halo, —O—R¹², —C(O)—R¹², C₁₋₆ alkyl, C₁₋₆ haloalkyl, and heterocyclyl.

In certain embodiments, R⁴ is heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof —CN, halo, —O—R¹², —C(O)—R¹², C₁₋₉ alkyl, C₁₋₉ haloalkyl, andheterocyclyl.

In certain embodiments, R⁴ is heterocyclyl optionally substituted withone to three substituents independently selected from the groupconsisting of —CN, halo, —O—R¹², —C(O)—R¹², C₁₋₉ alkyl, C₁₋₉ haloalkyl,and heterocyclyl.

In certain embodiments, R⁴ is heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof —CN, halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl, C₁₋₉haloalkyl, and heterocyclyl.

In certain embodiments, R⁴ is heterocyclyl optionally substituted withone to three substituents independently selected from the groupconsisting of —CN, halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl,C₁₋₉ haloalkyl, and heterocyclyl.

In certain embodiments, R⁴ is optionally substituted bicyclicheterocyclyl or optionally substituted bicyclic heteroaryl. In certainembodiments, R⁴ is

where Z⁴ is as defined herein, q is 0, 1, 2, 3 or 4, ring A is a 5- or6-membered cycloalkyl, heterocyclyl or heteroaryl ring, and ring B is a6-membered cycloalkyl, heterocyclyl or heteroaryl ring, provided that atleast one heteroatom is present in ring A or ring B such that R⁴ is anoptionally substituted bicyclic heterocyclyl or optionally substitutedbicyclic heteroaryl. In the above, the wavy line indicates the point ofattachment to the remainder of the molecule, where the attachment canthrough either ring (i.e., ring A or ring B) of the optionallysubstituted bicyclic heterocyclyl or optionally substituted bicyclicheteroaryl. In some embodiments, ring A and/or ring B comprisies an oxo(═O).

In certain embodiments, R⁴ is optionally substituted bicyclicheteroaryl. In certain embodiments, R⁴ is an optionally substitutedbicyclic heteroaryl selected from the group consisting of

and

where Z⁴ is as defined herein, q is 0, 1, 2, 3 or 4 and ring A is a 5-or 6-membered heterocyclyl or heteroaryl ring. In some embodiments, ringA comprisies an oxo (═O).

wherein Z⁴ is as defined herein and q is 0, 1, 2, 3 or 4.

In certain embodiments, R⁴ is

where Z⁴ is as defined herein and q is 0, 1, 2, 3 or 4.

In certain embodiments, the compound of Formula I is represented byFormula XII:

Wherein q, Z³, R¹, Z⁴, R⁵, and R⁶ are as defined herein, ring A ia a 5-or 6-membered heterocyclyl or heteroaryl and and Z⁹ is hydrogen, halo,—CN, or —O—R¹². In certain embodiments, the compound of Formula I isrepresented by Formula XIIA:

wherein q, Z³, R¹, Z⁴, R⁵, and R⁶ are as defined herein, ring A ia a 5-or 6-membered heterocyclyl or heteroaryl and and Z⁹ is hydrogen, halo,—CN, or —O—R¹².

In certain embodiments, the compound of Formula I is represented byFormula XIII:

wherein q, Z³, R¹, Z⁴, R⁵, and R⁶ are as defined herein and ring A ia a5- or 6-membered heterocyclyl or heteroaryl. In certain embodiments, thecompound of Formula I is represented by Formula XIIIA:

wherein q, Z³, R¹, Z⁴, R⁵, and R⁶ are as defined herein and ring A ia a5- or 6-membered heterocyclyl or heteroaryl.

In certain embodiments, the compound of Formula I is represented byFormula XIIIB:

wherein q, Z³, R¹, Z⁴, R⁵, and R⁶ are as defined herein.

In certain embodiments, the compound of Formula I is represented byFormula XIIIC:

wherein q, Z³, R¹, Z⁴, R⁵, and R⁶ are as defined herein.

In certain embodiments, the compound of Formula I is represented byFormula XIIID:

wherein q, Z³, R¹, Z⁴, R⁵, and R⁶ are as defined herein.

In certain embodiments, each Z⁴ is independently selected from the groupconsisting of —CN, halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl,C₁₋₉ haloalkyl, and heterocyclyl. In some embodiments, each Z⁴ isindependently selected from the group consisting of —CN, halo, —O—R¹²,and C₁₋₉ alkyl.

In certain embodiments, R⁴ is optionally substituted monocyclicheteroaryl. In certain embodiments, R⁴ is

where Z⁴ is as defined herein and q is 0, 1, 2, 3 or 4. In certainembodiments, R⁴ is

where Z⁴ is as defined herein. In certain embodiments, the compound ofFormula I is represented by Formula XIV:

wherein Z³, R¹, Z⁴, R⁵ and R⁶ are as defined herein. In certainembodiments, the compound of Formula I is represented by Formula XIVA:

wherein Z³, R¹, Z⁴, R⁵ and R⁶ are as defined herein.

In certain embodiments, Z³ is

In certain embodiments, each Z⁴ is independently selected from the groupconsisting of —CN, halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl,C₁₋₉ haloalkyl, and heterocyclyl. In some embodiments, each Z⁴ isindependently selected from the group consisting of —CN, halo, —O—R¹²,and C₁₋₉ alkyl. In certain embodiments of compounds of Formula IX or X,R¹ is C₁₋₉ alkyl, optionally substituted with one to three substituentsindependently selected the group consisting of halo, —CN, —O—R¹², C₁₋₉alkyl, and aryl. In certain embodiments of compounds of Formula IX or X,R⁶ is hydrogen. In certain embodiments of compounds of Formula IX or X,R⁵ is halo or cyano.

In one embodiment, R⁴ is

In one embodiment, R⁴ is

In one embodiment, R⁴ is

In one embodiment, R⁴ is

In one embodiment, R⁴ is

In certain embodiments, R⁴ is

S(O)₂N(R⁷)₂, —C(O)R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl; whereineach C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl,heterocyclyl, and heteroaryl may be optionally substituted with one tofour Z⁵.

In certain embodiments, R⁵ is hydrogen, halo, —CN, —C(O)R⁷, orheteroaryl. In one embodiment, R⁵ is —CN, halo or —O—R⁷. In certainembodiments, R⁵ is hydrogen, halo, —CN, —C(O)R⁷, —O—R⁷, —S(O)₂R⁷ orheteroaryl. In one embodiment, R⁵ is halo.

In certain embodiments, R is 1H-pyrazol-4-yl, 1-hydroxyethyl,1-methyl-1H-pyrazol-4-yl, 4-(acetylamino)phenyl, 6-fluoropyridin-3-yl,methyl acetyl, bromo, chloro, cyano, cyclopropyl, dimethylaminocarbonyl,ethynyl, fluoro, iodo, methoxy, methyl, hydroxyl, phenyl, pyridin-3-yl,pyridin-4-yl, pyrimidin-5-yl, acetyl, methylsulfonyl or trifluoromethyl.In one embodiment, R⁵ is chloro.

In one embodiment, m is 0. In another embodiment, m is 1.

In general, the specific compounds exemplified herein are named usingChemBioDraw Ultra. However, it is understood that other names may beused to identify compounds of the same structure. In particular, thecompounds may also be named using other nomenclature systems and symbolsthat are commonly recognized in the art of chemistry including, forexample, Chemical Abstract Service (CAS) and International Union of Pureand Applied Chemistry (IUPAC). Other compounds or radicals may be namedwith common names, or systematic or non-systematic names.

In certain embodiments, provided are optical isomers, racemates, orother mixtures thereof of the compounds described herein orpharmaceutically acceptable salts or a mixture thereof. In thosesituations, the single enantiomer or diastereomer, i.e., opticallyactive form, can be obtained by asymmetric synthesis or by resolution.Resolution can be accomplished, for example, by conventional methodssuch as crystallization in the presence of a resolving agent, orchromatography, using for example, a chiral high pressure liquidchromatography (HPLC) column.

Compositions provided herein that include a compound described herein orpharmaceutically acceptable salts, isomer, or a mixture thereof mayinclude racemic mixtures, or mixtures containing an enantiomeric excessof one enantiomer or single diastereomers or diastereomeric mixtures.All such isomeric forms of these compounds are expressly included hereinthe same as if each and every isomeric form were specifically andindividually listed.

A composition comprising a mixture of enantiomers (or diastereomers) ofa compound described herein or a pharmaceutically acceptable saltthereof, is also provided herein. In some embodiments, the compositioncomprises a single enantiomer of the compound and is substantially freeof the other enantiomer. In certain embodiments, the compound of FormulaI (or another Formula as described herein) contains one or moreadditional stereogenic atom(s) (e.g., at R¹ and/or R³). In suchinstances, the composition may contain a mixture of diastereomers. Insome embodiments, the composition comprises a single enantiomer of thecompound and is substantially free (i.e., having less than or about 40%,30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.05%, or 0.01%) of one or morediastereomers.

Accordingly, in certain embodiments, provided is a compositioncomprising a mixture of Formula IA, or a pharmaceutically acceptablesalt thereof, and Formula IB, or a pharmaceutically acceptable saltthereof.

wherein m, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁵ are as defined herein.

In one embodiment, the mixture is a racemic mixture. In otherembodiments, the composition comprises a mixture of Formula IA, or apharmaceutically acceptable salt thereof, and Formula IB, or apharmaceutically acceptable salt thereof, wherein Formula IA is presentin excess of over Formula IB, or a pharmaceutically acceptable saltthereof. In certain embodiments, provided is a composition substantiallyfree of Formula IB, having less than or about 40%, 30%, 25%, 20%, 15%,10%, 5%, 1%, 0.05%, or 0.01% of compounds of Formula IB.

In certain embodiments, provided here in is a composition comprising amixture of stereoisomers of a compound of Formula I:

wherein the mixture comprises compounds of Formula IA and IB in a ratioof at least about 3:1:

wherein m, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁵ are as defined herein.

The stereochemistry of the R⁴ group depicted in Formula IA may berepresented in an alternative way, provided that the configuration ofthe carbon atom to which it is attached is not altered. For example,compounds of Formula 1A may be depicted in any one of the equivalentrepresentations of Formula IA shown below.

In other embodiments, the mixture comprises compounds of Formula IA andIB in a a molar ratio of at least or about 3:1, at least or about 4:1,at least or about 5:1, at least or about 6:1, at least or about 7:1, atleast or about 8:1, at least or about 9:1, at least or about 10:1, atleast or about 11:1, at least or about 12:1, at least or about 20:1, atleast or about 30:1, at least or about 40:1, at least or about 80:1, atleast or about 160:1, or at least or about 320:1, respectively.

In certain embodiments, provided are also chelates, non-covalentcomplexes, and mixtures thereof, of the compounds described herein or apharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof. A “chelate” isformed by the coordination of a compound to a metal ion at two (or more)points. A “non-covalent complex” is formed by the interaction of acompound and another molecule wherein a covalent bond is not formedbetween the compound and the molecule. For example, complexation canoccur through van der Waals interactions, hydrogen bonding, andelectrostatic interactions (also called ionic bonding).

In certain embodiments, provided are prodrugs of the compounds describedherein. “Prodrug” refers to any compound that when administered to abiological system generates the drug substance, or active ingredient, asa result of spontaneous chemical reaction(s), enzyme catalyzed chemicalreaction(s), photolysis, and/or metabolic chemical reaction(s). Aprodrug is thus a covalently modified analog or latent form of atherapeutically active compound. Non-limiting examples of prodrugsinclude ester moieties, quaternary ammonium moieties, glycol moieties,and the like.

In certain embodiments, provided is a compound of Formula I, IA, IB, II,IIA, III, IIIA, IV, IVA, V, VA, VI, VIA, VII, VIIA, VIII, VIIIA, IX,IXA, X, XA, XI, XIA, XII,

where each R¹² is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or heterocyclyl;

-   -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups; and        each Z^(1b) is independently oxo, thioxo, hydroxy, halo, —NO₂,        —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl,        —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅        cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl), —O(heteroaryl),        —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl),        —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl),        —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂,        —N(C₃₋₁₅ cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂,        —N(C₃₋₁₅ cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂,        —N(heteroaryl)₂, —N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅        cycloalkyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆        alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈        haloalkyl), —N(C₁₋₉ alkyl)(aryl), —N(C₁₋₉ alkyl)(heteroaryl),        —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉ alkyl), —C(O)(C₂₋₆        alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅ cycloalkyl),        —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl), —C(O)(heteroaryl),        —C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl), —C(O)O(C₂₋₆ alkenyl),        —C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅ cycloalkyl), —C(O)O(C₁₋₈        haloalkyl), —C(O)O(aryl), —C(O)O(heteroaryl),        —C(O)O(heterocyclyl), —C(O)NH₂, —C(O)NH(C₁₋₉ alkyl),        —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl), —C(O)NH(C₃₋₁₅        cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl), —C(O)NH(aryl),        —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,        —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆        alkynyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂,        —C(O)N(aryl)₂, —C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂,        —NHC(O)(C₁₋₉ alkyl), —NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆        alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl), —NHC(O)O(C₂₋₆        alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl),        —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl),        —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl), —NHC(O)NH(C₂₋₆        alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈        haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),        —NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl), —S(C₂₋₆ alkenyl),        —S(C₂₋₆ alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈ haloalkyl),        —S(aryl), —S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl),        —N(C₁₋₉ alkyl)(S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆        alkynyl), —S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁₋₈ haloalkyl),        —S(O)(aryl), —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉        alkyl), —S(O)₂(C₂₋₆ alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        or —S(O)₂N(C₁₋₉ alkyl)₂;    -   wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl        is optionally substituted with one to four halo, C₁₋₉ alkyl,        C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉ alkyl), —NH(C₃₋₁₅        cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl), —NH(heteroaryl),        —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅ cycloalkyl)₂,        —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅        cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl),        —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),        —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl).

In certain embodiments, R⁶ is

and each R¹² is independently as defined herein.

In certain embodiments, R⁶ is

R⁶ also includes all individual stereoisomers, and mixtures thereof,including but not limited to, chirality at the phosphorous atom such asin the exemplary moieties shown above.

Also provided herein are the in vivo metabolic products of the compoundsdescribed herein. Such products may result, for example, from theoxidation, reduction, hydrolysis, amidation, esterification, and thelike, of the administered compound, primarily due to enzymaticprocesses.

Therapeutic Uses of the Compounds

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or a pharmaceutically acceptable salt,tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuteratedanalog thereof means an amount sufficient to effect treatment whenadministered to a subject, to provide a therapeutic benefit such asamelioration of symptoms or slowing of disease progression. For example,a therapeutically effective amount may be an amount sufficient todecrease a symptom of a disease or condition responsive to inhibition ofCot activity. The therapeutically effective amount may vary depending onthe subject, and disease or condition being treated, the weight and ageof the subject, the severity of the disease or condition, and the mannerof administering, which can readily be determined by one or ordinaryskill in the art.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. “Inhibition of activity of Cot” orvariants thereof refers to a decrease in activity in Cot as a direct orindirect response to the presence of a compound of the presentapplication relative to the activity Cot in the absence of the compoundof the present application. “Inhibition of Cot” refers to a decrease inCot activity as a direct or indirect response to the presence of acompound described herein relative to the activity of Cot in the absenceof the compound described herein. In some embodiments, the inhibition ofCot activity may be compared in the same subject prior to treatment, orother subjects not receiving the treatment.

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. Exemplary tissue samples includetumors and biopsies thereof. In this context, the compounds andcompositions described herein may be used for a variety of purposes,including therapeutic and experimental purposes. For example, thecompounds and compositions described herein may be used ex vivo todetermine the optimal schedule and/or dosing of administration of a Cotinhibitor for a given indication, cell type, individual, and otherparameters. Information gleaned from such use may be used forexperimental purposes or in the clinic to set protocols for in vivotreatment. Other ex vivo uses for which the compounds and compositionsdescribed herein may be suited are described below or will becomeapparent to those skilled in the art. The selected compounds may befurther characterized to examine the safety or tolerance dosage in humanor non-human subjects. Such properties may be examined using commonlyknown methods to those skilled in the art.

The compounds disclosed herein are useful for the treatment of diseasesor conditions mediated by Cot. Non-limiting examples of diseases orconditions mediated by Cot include, without limitation, cancer,diabetes, and inflammatory diseases such as rheumatoid arthritis (RA),multiple sclerosis (MS), inflammatory bowel disease (IBD), sepsis,psoriasis, misregulated TNF expression and graft rejection.

In further embodiments, the methods are provided for alleviating asymptom of a disease or disorder mediated by Cot. In some embodiments,the methods include identifying a mammal having a symptom of a diseaseor disorder mediated by Cot, and providing to the mammal an amount of acompound as described herein effective to ameliorate (i.e., lessen theseverity of) the symptom.

In some embodiments, the disease or condition mediated by Cot is a solidtumor. In particular embodiments, the solid tumor is from pancreaticcancer, bladder cancer, colorectal cancer, breast cancer, prostatecancer, renal cancer, hepatocellular cancer, lung cancer, ovariancancer, cervical cancer, gastric cancer, esophageal cancer, head andneck cancer, melanoma, neuroendocrine cancers, CNS cancers, brain tumors(e.g., glioma, anaplastic oligodendroglioma, adult glioblastomamultiforme, and adult anaplastic astrocytoma), bone cancer, or softtissue sarcoma. In some embodiments, the solid tumor is from non-smallcell lung cancer, small-cell lung cancer, colon cancer, CNS cancer,melanoma, ovarian cancer, renal cancer, prostate cancer, or breastcancer.

In some embodiments, the disease or condition mediated by Cot isdiabetes, which includes any metabolic disorder characterized byimpaired insulin production and glucose tolerance. In some embodiments,diabetes includes type 1 and type 2 diabetes, gestational diabetes,prediabetes, insulin resistance, metabolic syndrome, impaired fastingglycaemia and impaired glucose tolerance. Type 1 diabetes is also knownas Insulin Dependent Diabetes Mellitus (IDDM). Type 2 is also known asNon-Insulin-Dependent Diabetes Mellitus (NIDDM).

In some embodiments, the disease or condition mediated by Cot is aninflammatory disease or LPS induced endotoxin shock. In someembodiments, the disease is an autoimmune disease. In particularembodiments, the autoimmune disease is systemic lupus erythematosus(SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminatedencephalomyelitis, idiopathic thrombocytopenic purpura, multiplesclerosis (MS), inflammatory bowel disease (IBD), sepsis, psoriasis,Sjoegren's syndrome, autoimmune hemolytic anemia, asthma, or chronicobstructive pulmonary disease (COPD), ankylosing spondylitis, acute goutand ankylosing spondylitis, reactive arthritis, monoarticular arthritis,osteoarthritis, gouty arthritis, juvenile arthritis, juvenile onsetrheumatoid arthritis, juvenile rheumatoid arthritis or psoriaticarthritis. In other embodiments, the disease is inflammation. In yetother embodiments, the disease is excessive or destructive immunereactions, such as asthma, rheumatoid arthritis, multiple sclerosis,chronic obstructive pulmonary disease (COPD), and lupus.

In some embodiments, the disease or condition mediated by Cot isinflammatory bowel disease (IBD). The term “inflammatory bowel disease”or “IBD” as used herein is a collective term describing inflammatorydisorders of the gastrointestinal tract, the most common forms of whichare ulcerative colitis and Crohn's disease. Other forms of IBD that canbe treated with the presently disclosed compounds, compositions andmethods include diversion colitis, ischemic colitis, infectious colitis,chemical colitis, microscopic colitis (including collagenous colitis andlymphocytic colitis), atypical colitis, pseudomembranous colitis,fulminant colitis, autistic enterocolitis, indeterminate colitis,Behçet's disease, gastroduodenal CD, jejunoileitis, ileitis,ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome,mucositis, radiation induced enteritis, short bowel syndrome, celiacdisease, stomach ulcers, diverticulitis, pouchitis, proctitis, andchronic diarrhea.

Treating or preventing IBD also includes ameliorating or reducing one ormore symptoms of IBD. As used herein, the term “symptoms of IBD” refersto detected symptoms such as abdominal pain, diarrhea, rectal bleeding,weight loss, fever, loss of appetite, and other more seriouscomplications, such as dehydration, anemia and malnutrition. A number ofsuch symptoms are subject to quantitative analysis (e.g. weight loss,fever, anemia, etc.). Some symptoms are readily determined from a bloodtest (e.g. anemia) or a test that detects the presence of blood (e.g.rectal bleeding). The term “wherein said symptoms are reduced” refers toa qualitative or quantitative reduction in detectable symptoms,including but not limited to a detectable impact on the rate of recoveryfrom disease (e.g. rate of weight gain). The diagnosis is typicallydetermined by way of an endoscopic observation of the mucosa, andpathologic examination of endoscopic biopsy specimens.

The course of IBD varies, and is often associated with intermittentperiods of disease remission and disease exacerbation. Various methodshave been described for characterizing disease activity and severity ofIBD as well as response to treatment in subjects having IBD. Treatmentaccording to the present methods are generally applicable to a subjecthaving IBD of any level or degree of disease activity.

In some embodiments, the disease or condition treated by theadministration of a compound of composition described herein includesacute gout and ankylosing spondylitis, allergic disorders, Alzheimer'sdisease, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateralsclerosis and multiple sclerosis, atherosclerosis, bacterial infections,bone cancer pain and pain due to endometriosis, BRAF resistant melanoma,brain stem glioma or pituitary adenomas, burns, bursitis, cancer of theanal region, cancer of the endocrine system, cancer of the kidney orureter (e.g. renal cell carcinoma carcinoma of the renal pelvis), cancerof the penis, cancer of the small intestine, cancer of the thyroid,cancer of the urethra, cancers of the bloodsuch as acute myeloidleukemia, cancers of the tongue, carcinoma of the cervix, carcinoma ofthe endometrium, carcinoma of the fallopian tubes, carcinoma of therenal pelvis, carcinoma of the vagina or carcinoma of the vulva, chronicmueloid leukemia, chronic or acute leukemia, chronic pain, classicBartter syndrome, common cold conjunctivitis, coronary heart disease,cutaneous or intraocular melanoma, dermatitis, dysmenorrhea, eczema,endometriosis, familial adenomatous polyposis, fibromyalgia, fungalinfections, gout, gynecologic tumors, uterine sarcomas, carcinoma of thefallopian tubes, headache, hemophilic arthropathy, Parkinson's disease,AIDS, herpes zoster, Hodgkin's disease, Huntington's, hyperprostaglandinE syndrome, influenza, iritis, juvenile arthritis, juvenile onsetrheumatoid arthritis, juvenile rheumatoid arthritis, low back and neckpain, lynphocytic lymphomas, myofascial disorders, myositis, neuralgia,neurodegenerative disorders such as Alzheimer's disease,neuroinflammatory disorders, neuropathic pain, carcinoma of the vulva,Parkinson's disease, pediatric malignancy, pulmonary fibrosis rectalcancer, rhinitis, sarcoidosis, sarcomas of soft tissues, scleritis, skincancer, solid tumors of childhood, spinal axis tumors, sprains andstrains, stomach cancer, stroke, subacute and chronic musculoskeletalpain syndromes such as bursitis, surgical or dental procedures, symptomsassociated with influenza or other viral infections, synovitis,toothache, ulcers, uterine cancer, uterine sarcomas, uveitis,vasculitis, viral infections, viral infections {e.g. influenza) andwound healing.

Criteria useful for assessment of disease activity in subjects withulcerative colitis can be found in, e.g., Truelove et al. (1955) Br MedJ 2:1041-1048.) Using these criteria, disease activity can becharacterized in a subject having IBD as mild disease activity or severedisease activity. Subjects who do not meet all the criteria for severedisease activity, and who exceed the criteria for mild disease activityare classified as having moderate disease activity.

The presently disclosed treatment methods can also be applied at anypoint in the course of the disease. In certain embodiments, the methodsare applied to a subject having IBD during a time period of remission(i.e., inactive disease). In such embodiments, the present methodsprovide benefit by extending the time period of remission (e.g.,extending the period of inactive disease) or by preventing, reducing, ordelaying the onset of active disease. In other embodiments, methods maybe applied to a subject having IBD during a period of active disease.Such methods provide benefit by reducing the duration of the period ofactive disease, reducing or ameliorating one or more symptoms of IBD, ortreating IBD.

Measures for determining efficacy of treatment of IBD in clinicalpractice have been described and include, for example, the following:symptom control; fistula closure; extent of corticosteroid therapyrequired; and, improvement in quality of life. Heath-related quality oflife (HRQL) can be assessed using the Inflammatory Bowel DiseaseQuestionnaire (IBDQ), which is extensively used in clinical practice toassess quality of life in a subject with IBD. (See Guyatt et al. (1989)Gastroenterology 96:804-810.) In some embodiments, the disease orcondition is immune-mediated liver injury, disease or condition. Tpl2can mediate immune related liver diseases or conditions. (Vyrla et. al.,The Journal of Immunology, 2016, 196; Perugorria et. al., Hepatology,2013; 57:1238-1249)

In some embodiments, the disease or condition mediated by Cot isalcoholic hepatitis. Alcoholic hepatitis is a clinical syndromecharacterized by jaundice and liver failure that develops in subjectswith chronic and active alcohol abuse. (See Akriviadis E. et. al, AnnGastroenterol. 2016 April-June; 29(2): 236-237). Alcoholic hepatitis cancause cirrhosis and fibrosis of the liver cells. Glucocorticoids, (e.g.prednisolone) and phosophodiesterase inhibitors (e.g. pentoxifylline)can be used to treat alcoholic hepatitis. The compounds herein can beused as stand-alone treatments or in combination with the currenttreatments for alcoholic hepatitis.

In some embodiments, the disease or condition mediated by Cot issystemic lupus erythematosus (SLE), lupus nephritis, lupus-related, orother autoimmune disorders or a symptom of SLE. Symptoms of systemiclupus erythematosus include joint pain, joint swelling, arthritis,fatigue, hair loss, mouth sores, swollen lymph nodes, sensitivity tosunlight, skin rash, headaches, numbness, tingling, seizures, visionproblems, personality changes, abdominal pain, nausea, vomiting,abnormal heart rhythms, coughing up blood and difficulty breathing,patchy skin color and Raynaud's phenomenon.

Improvements in any of the foregoing response criteria are specificallyprovided by the methods of the present disclosure.

Combination Therapies

In one embodiment, the compounds disclosed herein may be used incombination with one or more additional therapeutic agent that are beingused and/or developed to treat inflammatory disorders (e.g., IBD). Theone or more additional therapeutic agent may be a α4β7 inhibitor, asteroid, a MMP-9 antibody, a S1P1 agonist, a TNF biologic, or anycombination thereof.

In some embodiments, the one or more additional therapeutic agent may bea α4β7 integrin inhibitor, or an agent that inhibits the expressionand/or activity of α4β7 integrin. The inhibitor can be small molecule orbiologic. For example, the α4β7 integrin inhibitor can be natalizumab orvedolizumab.

In some embodiments, the one or more additional therapeutic agent may bea steroid, including but not limited to, corticosteroids.Corticosteroids may be administered by various routes, includingintravenously (i.e., methylprednisolone, hydrocortisone), orally (i.e.,prednisone, prednisolone, budesonide, dexamethasone), or topically(i.e., enema, suppository, or foam preparations).

In some embodiments, the one or more additional therapeutic agent may bean MMP9 inhibitor, or an agent that inhibits the expression and/oractivity of MMP9. A representative protein sequence for MMP9 is GenBankAccession No. NP_004985. The inhibitor can be small molecule orbiologic. For instance, Gu et al., The Journal of Neuroscience, 25(27):6401-6408 (2005) discloses a specific MMP9 inhibitor, SB-3CT (CAS292605-14-2). Further, siRNA, antisense RNA and antibodies have alsobeen demonstrated to inhibit the expression or activity of MMP9 and arewithin the scope of the present disclosure. In one embodiment, an MMP9inhibitor is a monoclonal anti-MMP9 antibody. In some embodiment, theone or more additional therapeutic agent includes an MMP9 inhibitor anda nucleoside analog such as gemcitabine.

In some embodiments, the one or more additional therapeutic agent may bea Sphingosine 1-Phosphate Receptor (S1P1) inhibitor, or an agent thatinhibits the expression and/or activity of S1P1. The inhibitor can besmall molecule or biologic. For example, the S1P1 inhibitor can beRPC1063.

In some embodiments, the one or more additional therapeutic agent may bea TNF inhibitor, or an agent that inhibits the expression and/oractivity of TNF. The inhibitor can be small molecule or biologic. Forexample, the TNF inhibitor can be golimumab.

In some embodiments, the one or more additional therapeutic agent isbeing used and/or developed to treat ulcerative colitis (UC) and/orCrohn disease (CD). The agent can be a biologic or small molecule. Insome embodiments, the agent is a modulator (e.g., agonist or antagonist)of S1P1, IL-6, CX3CL1, DHODH, α4, β7, JAK, TNF, CB, IL-12/IL-23, CCL20,TLR9, MAdCAM, CCR9, CXCL10, Smad7, PDE4, MC, VLA-1, GC, GATA-3, Eotaxin,FFA2, LIGHT, FMS, MMP9, CD40, Steroid, 5-ASA, Immunomod, STAT3, and/orEP4.

Non-limiting examples of agents being used and/or developed to treatulcerative colitis (UC) include GSK3050002 (CCL20 modulator, by GSK),GS-5745 (MMP9 modulator, by Gilead), AVX-470 (TNF modulator, by Avaxia),Bertilimumab (Eotaxin modulator, by Immune Pharma), Simponi (TNFmodulator, by Johnson & Johnson and Merck), RX-10001 (by Resolvyx),IBD-98 (5-ASA modulator, by Holy Stone), SP-333 (GC modulator, bySynergy), KAG-308 (EP4 modulator, by Kaken), SB012 (GATA-3 modulator, bySterna), AJM300 (α4 modulator, by Ajinomoto), BL-7040 (TLR9 modulator,by BiolineRx), TAK-114 (SAT3 modulator, by Takeda), CyCol (by Sigmoid),GWP-42003 (CB modulator, by GW Pharma), ASP3291 (MC modulator, byDrais), GLPG0974 (FFA2 modulator, by Galapagos), Ozanimod (S1P1modulator, by Receptos), ASP015K (JAK modulator, by Astellas),Apremilast (PDE4 modulator, by Celgene), Zoenasa (by Altheus),Kappaproct (TLR9 modulator, by InDex), Phosphatidylcholine (by DrFalk/Lipid Tx), Tofacitinib (JAk modulator, by Pfizer), Cortment(Steroid modulator, by Ferring), Uceris (Steroid modulator, by Salix),and 5-ASA modulators such as Delzicol (by Actavis), Canasa (by Aptalis),Asacol (by Actavis), Pentasa (by Shire/Ferring), Lialda (by Shire),Mezavant (by Shire), Apriso (by Salix), Colazal (by Salix), Giazo (bySalix), and Salofalk (by Dr Falk). Non-limiting examples of agents beingused and/or developed to treat Crohn disease (CD) include FFP102 (CD40modulator, by Fast Forward), E6011 (CX3CL1 modulator, by Eisai),PF-06480605 (by Pfizer), QBECO SSI (Immunomod modulator, by QuBiologics), PDA-001 (by Celgene), BI 655066 (IL-12/IL-23 modulator, byBoehringer), TNFα kinoid (TNF modulator, by Neovacs), AMG 139/MEDI-2070(IL-12/IL-23 modulator, by AstraZeneca), PF-04236921 (IL-6 modulator, byPfizer), Tysabri (β7 modulator, marketed by Biogen Idec in the U.S.),Cimzia (marketed by UCB in the U.S.), JNJ-40346527 (FMS modulator, byJ&J), SGX-203 (Steroid modulator, by Solgenix), CyCron (by Sigmoid),CCX507 (CCR9 modulator, by ChemoCentryx), MT1303 (S1P1 modulator, byMitsubishi), 6-MP (by Teva), ABT-494 (JAk modulator, by Abbvie),Tofacitinib (JAk modulator, by Pfizer), GLPG0634 (JAk modulator, byGalapagos), TRK-170 ((37 modulator, by Toray), Mongersen (Smad7modulator, by Celgene), RHB-104 (by Redhill), Rifaxmin EIR (by Salix),Budenofalk (by Dr Falk), and Entocort (by AstraZeneca).

Non-limiting examples of agents being used and/or developed to treatulcerative colitis (UC) and Crohn disease (CD) include PF-06410293 (byPfizer), SAN-300 (VLA-1 modulator, by Salix), SAR252067 (LIGHTmodualtor, by Sanofi), PF-00547659 (MAdCAM modualtor, by Pfizer),Eldelumab (Smad7 modulator, by BMS), AMG 181/MEDI-7183 (β7 modulator, byAmgen/AstraZeneca), Etrolizumab (β7 modulator, by Roche), Ustekinumab(IL-12/IL-23 modulator, by J&J), Remicade (TNF modulator, by J&J andMerck), Entyvio (β7 modulator, by Takeda), Humira (TNF modulator, byAbbvie), Infliximab (by Celtrion), PF-06651600 (by Pfizer), GSK2982772(by GSK), GLPG1205 (FFA2 modulator, by Galapagos), AG014 (by Intrexon)and Vidofludimus (DHODH modulator, by 4SC).

In some embodiments, the one or more additional therapeutic agent may bea JAK inhibitor, particularly a JAK-1 selective inhibitor. The inhibitorcan be small molecule or biologic. For example, the JAK inhibitor can beFilgotinib, GLPG0634 (JAK modulator, by Galapagos).

Kits

Provided herein are also kits that include a compound of Formula I, or apharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof, and suitablepackaging. In one embodiment, a kit further includes instructions foruse. In one aspect, a kit includes a compound of Formula I (or any otherFormula described herein), or a pharmaceutically acceptable salt,tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuteratedanalog thereof, and a label and/or instructions for use of the compoundsin the treatment of the indications, including the diseases orconditions, described herein.

Provided herein are also articles of manufacture that include a compounddescribed herein or a pharmaceutically acceptable salt, tautomer,stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogthereof in a suitable container. The container may be a vial, jar,ampoule, preloaded syringe, and intravenous bag.

Pharmaceutical Compositions and Modes of Administration

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provided herein are alsopharmaceutical compositions that contain one or more of the compoundsdescribed herein or a pharmaceutically acceptable salt, tautomer,stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogthereof and one or more pharmaceutically acceptable vehicles selectedfrom carriers, adjuvants and excipients. Suitable pharmaceuticallyacceptable vehicles may include, for example, inert solid diluents andfillers, diluents, including sterile aqueous solution and variousorganic solvents, permeation enhancers, solubilizers and adjuvants. Suchcompositions are prepared in a manner well known in the pharmaceuticalart. See, e.g., Remington's Pharmaceutical Sciences, Mace PublishingCo., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, MarcelDekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical composition may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In certain embodiments, the pharmaceuticalcomposition may be administered by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds described herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound described herein or apharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof, the activeingredient is usually diluted by an excipient and/or enclosed withinsuch a carrier that can be in the form of a capsule, sachet, paper orother container. When the excipient serves as a diluent, it can be inthe form of a solid, semi-solid, or liquid material, which acts as avehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, sterile injectable solutions, and sterile packagedpowders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions that include at least one compound described herein ora pharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof can be formulatedso as to provide quick, sustained or delayed release of the activeingredient after administration to the subject by employing proceduresknown in the art. Controlled release drug delivery systems for oraladministration include osmotic pump systems and dissolutional systemscontaining polymer-coated reservoirs or drug-polymer matrixformulations. Examples of controlled release systems are given in U.S.Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Anotherformulation for use in the methods disclosed herein employ transdermaldelivery devices (“patches”). Such transdermal patches may be used toprovide continuous or discontinuous infusion of the compounds describedherein in controlled amounts. The construction and use of transdermalpatches for the delivery of pharmaceutical agents is well known in theart. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein or a pharmaceutically acceptable salt,tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuteratedanalog thereof. When referring to these preformulation compositions ashomogeneous, the active ingredient may be dispersed evenly throughoutthe composition so that the composition may be readily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation may include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedherein. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect. In otherembodiments, compositions in pharmaceutically acceptable solvents may benebulized by use of inert gases. Nebulized solutions may be inhaleddirectly from the nebulizing device or the nebulizing device may beattached to a facemask tent, or intermittent positive pressure breathingmachine. Solution, suspension, or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

Dosing

The specific dose level of a compound of the present application for anyparticular subject will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of acompound described herein per kilogram of the subject's body weight(mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate.In some embodiments, about 0.1 and 100 mg/kg may be appropriate. Inother embodiments a dosage of between 0.5 and 60 mg/kg may beappropriate. Normalizing according to the subject's body weight isparticularly useful when adjusting dosages between subjects of widelydisparate size, such as occurs when using the drug in both children andadult humans or when converting an effective dosage in a non-humansubject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compounddescribed herein administered per dose or per day. Daily dosage of acompound of Formula I may be between about 1 mg and 4,000 mg, betweenabout 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, betweenabout 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to200 mg/day, or between about 15 to 150 mg/day.

When administered orally, the total daily dosage for a human subject maybe between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, betweenabout 10-500 mg/day, between about 50-300 mg/day, between about 75-200mg/day, or between about 100-150 mg/day.

The compounds of the present application or the compositions thereof maybe administered once, twice, three, or four times daily, using anysuitable mode described above. Also, administration or treatment withthe compounds may be continued for a number of days; for example,commonly treatment would continue for at least 7 days, 14 days, or 28days, for one cycle of treatment. Treatment cycles are well known incancer chemotherapy, and are frequently alternated with resting periodsof about 1 to 28 days, commonly about 7 days or about 14 days, betweencycles. The treatment cycles, in other embodiments, may also becontinuous.

In a particular embodiment, the method comprises administering to thesubject an initial daily dose of about 1 to 800 mg of a compounddescribed herein and increasing the dose by increments until clinicalefficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg canbe used to increase the dose. The dosage can be increased daily, everyother day, twice per week, or once per week.

Synthesis of the Compounds of Formula I

The compounds may be prepared using the methods disclosed herein androutine modifications thereof, which will be apparent given thedisclosure herein and methods well known in the art. Conventional andwell-known synthetic methods may be used in addition to the teachingsherein. The synthesis of typical compounds described herein may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g., from Sigma Aldrich orother chemical suppliers.

General Synthesis

Typical embodiments of compounds described herein may be synthesizedusing the general reaction schemes described below. It will be apparentgiven the description herein that the general schemes may be altered bysubstitution of the starting materials with other materials havingsimilar structures to result in products that are correspondinglydifferent. Descriptions of syntheses follow to provide numerous examplesof how the starting materials may vary to provide correspondingproducts. Given a desired product for which the substituent groups aredefined, the necessary starting materials generally may be determined byinspection. Starting materials are typically obtained from commercialsources or synthesized using published methods. For synthesizingcompounds which are embodiments described in the present disclosure,inspection of the structure of the compound to be synthesized willprovide the identity of each substituent group. The identity of thefinal product will generally render apparent the identity of thenecessary starting materials by a simple process of inspection, giventhe examples herein. In general, compounds described herein aretypically stable and isolatable at room temperature and pressure.

Synthetic Reaction Parameters

The compounds of this disclosure can be prepared from readily availablestarting materials using, for example, the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts (1999) Protecting Groups inOrganic Synthesis, 3rd Edition, Wiley, New York, and references citedtherein.

Furthermore, the compounds of this disclosure may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis disclosure, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989)organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989).

The term “solvent” generally refers to a solvent inert under theconditions of the reaction being described in conjunction therewith(including, for example, benzene, toluene, acetonitrile, tetrahydrofuran(THF), dimethylformamide (DMF), chloroform, methylene chloride (ordichloromethane), diethyl ether, methanol, and the like). Unlessspecified to the contrary, the solvents are inert organic solvents, andthe reactions may carried out under an inert gas, preferably argon ornitrogen.

The term “q.s.” means adding a quantity sufficient to achieve a statedfunction, e.g., to bring a solution to the desired volume (i.e., 100%).

The compounds of Formula I may prepared by first providing thesubstituted quinoline core, and optionally further modifying the core asdesired to provide the substituents disclosed herein. Scheme 1 shows thepreparation of the quinoline core to provide compounds of Formula 1-e,where m, R⁵ and R¹⁵ are as defined herein, or is a functional group thatmay be converted thereto using standard reaction conditions.

In Scheme 1, suitably substituted 1-a and 1-b are condensed in asuitable solvent (e.g., DMF, etc.) in the presence of catalyst (e.g.,Cs₂CO₃, etc.) at an elevated temperature (e.g., about 40-50° C.) toprovide 1-c. Compound 1-c is then converted to 1-d under thermalcyclization conditions (i.e., about 250° C.) or under microwaveconditions. Chlorination of 1-d to provide 1-e is achieved using asuitable chlorinating agent (e.g., POCl₃, SOCl₂, etc.) at an elevatedtemperature (e.g., about 110-120° C.) in the presence of a base (e.g.pyridine, dimethylaniline, diethylaniline, etc.) or a catalyst (e.g.,DMF, DEF, etc.) and in a suitable solvent (e.g. chlorobenzene, CH₃CN,etc.) or solvent-free conditions (i.e., neat).

Scheme 2 shows the synthesis of compounds of Formula 2-c and 2-d wherem, R¹, R², R⁵ and R¹⁵ are as defined herein.

In Scheme 2, 1-e is reacted with a suitable amine under standardnucleophilic aromatic substitution conditions in the presence of a base(e.g., NEt₃, etc.) and at elevated temperature (e.g., 150° C.) to obtain2-a. Compounds of Formula I where R⁵ and/or R¹⁵ is cyano are provided byreacting 2-a with a suitable cyanating agent (e.g., CuCN, Zn(CN)₂, etc.)in the presence of a catalyst (e.g., palladium, nickel, copper, etc.).Compounds 2-c and 2-d are then provided via reduction of the nitro groupof compounds 2-a or 2-b, respectively (using e.g., Fe, SnCl₂, etc.).

Scheme 3 shows the synthesis of compounds 3-d and 3-e, where R⁴ is asdefined herein.

In Scheme 3, deuterated 3-c is provided by reducing suitably substitutedaldehyde 3-a with a deuteride-containing reducing agent (e.g., NaBD₄),followed by oxidation of 3-b to the corresponding aldehyde 3-c understandard oxidizing conditions (e.g., MnO₂, Fe₂O₃, NiO, CuO, ZnO, ZrO₂,La₂O₃, Sm₂O₃, Eu₂O₃, Yb₂O₃, etc.). Compound 3-d is obtained in two stepsby reaction of 3-c with ethynyl Grignard, followed by acylation of theresulting alcohol with acetic anhydride in the presence of a base (e.g.,pyridine, TEA, etc.). Compound 3-e is provided in a similar two-stepprocess by reacting suitably substituted aldehyde 3-a with ethynylGrignard, followed by acylation of the resulting alcohol with aceticanhydride.

Scheme 4 shows the synthesis of suitably protected azide compounds ofFormula 4-b, where Lg is a leaving group and Z³ is as defined herein.

In Scheme 4, suitably substituted amine 4-a is treated with a diazotransfer agent (e.g., imidazole-1-sulfonyl azide hydrochloride) toafford corresponding 4-b. Alternatively, 4-b may be obtained in twosteps from alcohol 4-c by conversion of the hydroxyl moiety to asuitable leaving group (Lg) (e.g., TsO—, MsO—, NsO—, TfO—, etc.)followed by nucleophilic displacement with azide.

Scheme 5 shows the synthesis of intermediate compounds of Formula 5-c,where R⁵⁰ is alkyl and Z³ is as defined herein.

In Scheme 5, suitably substituted triazole 5-b is obtained by reactionof 4-b with 5-a using standard 1,3-dipolar cycloaddition conditions.Acetal 5-b is converted to the corresponding aldehyde 5-c under standardcarbonyl deprotection conditions (e.g., aqueous acid).

Scheme 6 shows a general synthesis of exemplary compounds of Formula I,where Z³, m, R¹, R², R⁴, R⁵ and R¹⁵ and are as defined herein.

In Scheme 6, compounds of Formula 6-c can be provided via N-alkylationof amine 2-d with 3-d (or 3-e), followed by cyclization with azide 4-bunder standard 1,3-dipolar cycloaddition conditions. Separation of theisomers of Formula 6-a to give compounds of Formula 6-b can be performedusing standard chiral separation/resolution techniques (e.g., chiralchromatography, crystallization, etc.). Alternatively, compounds ofFormula 6-b can be provided via enantioselective N-alkylation of 2-dwith 3-d (or 3-e) using a chiral metal complex (e.g., [Cu(CH₃CN)₄]PF₆,CuOTf.benzene, Cu(OAc)₂, or Cu(I)I, etc., with a chiral ligand).Suitable reaction conditions and exemplary chiral ligands/complexes canbe found in the literature (see, e.g., Detz, et al. Angew. Chem. Int.Ed. 2008, 47, 3777-3780). Contacting compound 6-c with azide 4-b understandard 1,3-dipolar cycloaddition conditions provide compound 6-b. 6-cmay or may not be isolated prior to the addition of compound 4-b.

Scheme 7 shows an alternate synthesis of compounds of Formula I viaimine formation and subsequent nucleophilic addition, where Z³, m, R¹,R², R³, R⁴, R⁵ and R¹⁵ are as defined herein.

In Scheme 7, amine 2-d is reacted with aldehyde 7-a to afford thecorresponding imine 7-b under standard imine-forming conditions.Compound 7-b is then reacted with Grignard reagent 7-c to provideFormula I. Alternatively, 2-d can be reacted with aldehyde 7-d to affordimine 7-e, which is then reacted with ethynyl Grignard to providecompound 7-f. Compound 7-f can then be converted to compound 7-g understandard 1,3-dipolar cycloaddition conditions with 4-b as shown inScheme 6. Further, resolution of the isomers of Formula I or compound7-g can be performed using standard chiral separation/resolutionconditions (e.g., chiral chromatography, crystallization, etc.).

Scheme 8 shows another alternate general synthesis of compounds ofFormula I, where m, R¹, R², R³, R⁴, R⁵ and R¹⁵ are as defined herein.

In Scheme 8, amine 2-d is reacted with appropriately substituted 8-aunder nucleophilic substitution conditions, where Lg is a suitableleaving group, such as a halide (e.g., fluoro, chloro, bromo, iodo) oran activated alcohol (e.g., AcO—, TsO—, TfO—, MsO—, etc.) in thepresence of a base, to provide compound of Formula I. Alternatively,amine 2-d is reacted with ketone 8-b to provide 8-c, which issubsequently reduced to provide compound of Formula I. Resolution of theisomers of Formula I can be performed using standard chiralseparation/resolution conditions (e.g., chiral chromatography,crystallization, etc.).

EXAMPLES

The following examples are included to demonstrate specific embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques to function well in the practice of the disclosure, and thuscan be considered to constitute specific modes for its practice.However, those of skill in the art should, in light of the presentdisclosure, appreciate that many changes can be made in the specificembodiments which are disclosed and still obtain a like or similarresult without departing from the spirit and scope of the disclosure.

LIST OF ABBREVIATIONS AND ACRONYMS

Abbreviation Meaning ° C. Degree Celsius Ac Acetyl aq. Aqueous ATPAdenosine triphosphate BOC tert-Butoxycarbonyl br Broad BSA Bovine serumalbumin Cbz Carboxybenzyl COD Cyclooctadiene COPD Chronic obstructivepulmonary disease Cp Cyclopentadienyl d Doublet DABCO1,4-Diazabicyclo[2.2.2]octane DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCEDichloroethene DCM Dichloromethane dd Doublet of doublets DEFN,N-Diethylformamide DMF Dimethylformamide DMSO Dimethylsulfoxide dppf1,1′-Bis(diphenylphosphino)ferrocene dt Doublet-triplet DTTDithiothreitol EC₅₀ The half maximal effective concentration EGFREpidermal growth factor receptor eq Equivalents ES/MS Electrospray massspectrometry Et Ethyl FBS Fetal bovine serum g Grams HEPES2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid HPLC Highpressure liquid chromatography hrs Hours Hz Hertz IBD Inflammatory boweldisease i-pr Isopropyl J Coupling constant (MHz) Kg/kg Kilogram LCMSLiquid chromatography-mass spectrometry LPS Lipopolysaccharide M Molar mmultiplet M+ Mass peak M + H+ Mass peak plus hydrogen Me Methyl mgMilligram MHz Megahertz min Minute ml/mL Milliliter mM Millimolar mmolMillimole MOPS 3-Morpholinopropane-1-sulfonic acid MS Mass spectroscopyMs Mesyl nBu/Bu Butyl nL Nanoliter nm Nanometer NMR Nuclear magneticresonance NP-40 Nonyl phenoxypolyethoxylethanol Ns Nosyl Pd-C/Pd/CPalladium on Carbon pg Pictogram Ph Phenyl PPTS Pyridiniump-toluenesulfonate PS Polystyrene p-TSOH/pTSA p-Toluenesulfonic acid qQuartet q.s. Quantity sufficient to achieve a stated function RBF Roundbottom flask RP Reverse phase RPMI Roswell Park Memorial Institutemedium rt Room temperature s Singlet sat. Saturated t Triplet TBAFTetra-n-butylammonium fluoride TBS tert-Butyldimethylsilyl t-Butert-Butyl TC Thiophene-2-carboxylate TEA Triethanolamine TfTrifluoromethanesulfonyl TFA Trifluoroacetic acid THF TetrahydrofuranTpl-2 Tumor Progression Locus 2 TR-FRET Time-resolved fluorescenceenergy transfer Ts Tosyl δ Chemical shift (ppm) μL/μl Microliter μMMicromolar

Intermediates Example Synthesis of a Cyanoquinolinecore

A mixture of 2-chloro-4-nitroaniline (1 eq), (Z)-ethyl2-cyano-3-ethoxyacrylate (1.3 eq) and Cs₂CO₃ (1.3 eq) in DMF was heatedat 45° C. overnight. After being cooled to room temperature, the mixturewas poured into water. The formed solid was filtered, and washed withwater and dried to give the title compound as a solid which was used forthe next step without further purification. ¹H NMR (DMSO-d₆, 300 MHz): δ11.28 (d, J=12.9 Hz, 1H), 8.84 (d, J=12.9 Hz, 1H), 8.42 (d, J=2.4 Hz,1H), 8.26-8.22 (m, 1H), 8.02 (d, J=9.3 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H),1.27 (t, J=7.2 Hz, 3H).

Synthesis of 8-Chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile

A suspension of (Z)-ethyl3-((2-chloro-4-nitrophenyl)amino)-2-cyanoacrylate in diphenyl etherunder nitrogen was heated to reflux with a sand bath in a heating mantlefor 24 hours. After cooling to room temperature, the reaction mixturewas poured into hexane and stirred for 2 hours. The mixture was filteredand the filter cake was washed with hexane twice to give title compoundas a brown solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 12.86 (br s, 1H),8.73-8.71 (m, 3H).

Synthesis of 4,8-Dichloro-6-nitroquinoline-3-carbonitrile

A suspension of8-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile and fivedrops of DMF in POCl₃ was heated at 115° C. overnight. The brown clearsolution was cooled down to room temperature and excess of POCl₃ wasremoved. The residue was dissolved in DCM, washed with sat. NaHCO₃,brine and dried over Na₂SO₄. The solution was filtered and concentratedto give a crude product. The residue was triturated with hexane andEtOAc to afford the title compound as a brown solid. ¹H NMR (DMSO-d₆,300 MHz): δ 9.50 (s, 1H), 8.98 (d, J=2.4 Hz, 1H), 8.89 (d, J=2.4 Hz,1H).

Example Alkynylacetate

1-(6-fluoropyridin-3-yl)prop-2-yn-1-yl acetate

6-fluoronicotinaldehyde (300 mg, 2.40 mmol) was dissolved in THF (15 mL)and brought to 0° C. Ethynylmagnesium bromide (0.5 M in THF, 5.76 mL,2.88 mmol) was added slowly and the resulting solution allowed to stirfor 30 minutes. Acetic anhydride (0.45 mL, 4.80 mmol) was then added,the cold bath removed, and the reaction mixture allowed to warm to roomtemperature over 2 hours. The reaction contents were quenched by theaddition of saturated aqueous NH₄Cl (5 mL), poured into water (5 mL),and extract with EtOAc (3×15 mL). The combined organic phase was washedwith brine (10 mL), dried over MgSO₄ and concentrated. The crude residuewas purified by flash chromatography (eluent: EtOAc/hexanes) to give thedesired product.

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)prop-2-yn-1-yl acetate (200 mg,0.83 mmol) was dissolved in DMF (2 mL) after which cesium carbonate (405mg, 1.2 mmol) and 2-iodopropane (211 mg, 1.2 mmol) were added and theresulting mixture stirred at 25° C. under ambient atmosphere overnight.The reaction mixture was poured into water (3 mL) and extracted withEtOAc (3×5 mL). The organic layer was dried over MgSO₄, filtered,concentrated, and purified by via silica gel chromatography (eluent:EtOAc/hexanes) to give the N-alkylated product. Note: The samealkylation protocol could be performed on the preceding1-oxo-1,2-dihydroisoquinoline-5-carbaldehyde.

Example Aldehydes for Alkynyl Acetate Synthesis

6-fluoronicotin-aldehyde-α-D

6-fluoronicotinaldehyde (1.14 g, 9.11 mmol) was dissolved in MeOH (8 mL)at room temperature. NaBD₄ (458 mg, 10.9 mmol) was then added as asingle portion and the reaction mixture stirred for 20 minutes. Thereaction mixture was carefully quenched with water (5 mL) and extractedwith EtOAc (3×15 mL). The combined organic layers were washed with brine(5 mL), dried over MgSO₄ and concentrated to give crude alcohol whichwas carried forward without further purification. The crude alcohol wasre-dissolved in DCM (40 mL) and manganese(IV) oxide (19.9 g, 281 mmol)was added at room temperature. After 2 hours the reaction mixture wasfiltered through a pad of celite rinsing with DCM and EtOAc. Thefiltrate was then concentrated to give the desired product withapproximately 95% deuterium incorporation.

2-acetyl-3-oxoisoindoline-4-carbaldehyde

3-oxoisoindoline-4-carbaldehyde (300 mg, 1.86 mmol) was dissolved in THF(5 mL) at room temperature. Acetic anhydride (0.53 mL, 5.59 mmol) andDMAP (45 mg, 0.37 mmol) were added and the reaction mixture stirredovernight. The reaction contents were quenched by the addition ofsaturated aqueous NH₄Cl (3 mL), poured into water (3 mL), and extractedwith EtOAc (3×8 mL). The combined organic phases were washed with brine(5 mL), dried over MgSO₄ and concentrated. The crude residue waspurified by flash chromatography (eluent: EtOAc/hexanes) to give thedesired product.

tert-butyl (7-formylbenzo[d]thiazol-2-yl)carbamate

ethyl 2-((tert-butoxycarbonyl)amino)benzo[d]thiazole-7-carboxylate

ethyl 2-aminobenzo[d]thiazole-7-carboxylate (300 mg, 1.35 mmol),di-tert-butyl dicarbonate (0.34 mL, 1.49 mmol) and DMAP (181 mg, 1.49mmol) were dissolved in DCM (10 mL) and stirred at room temperature for3 hours. The reaction mixture was then poured into water (10 mL) andextracted with DCM (2×20 mL). The combined organic extracts were driedover MgSO₄, concentrated, and purified by flash chromatography (eluent:EtOAc/hexanes) to give the desired product.

tert-butyl (7-(hydroxymethyl)benzo[d]thiazol-2-yl)carbamate

ethyl 2-((tert-butoxycarbonyl)amino)benzo[d]thiazole-7-carboxylate (204mg, 0.63 mmol) was dissolved in THF (7 mL) and brought to 0° C. LiAlH₄(72 mg, 1.90 mmol) was added portionwise and the reaction mixtureallowed to stir for 90 minutes. The reaction mixture was quenched at 0°C. carefully with water (5 mL) and extracted with EtOAc (3×8 mL). Thecombined organic phases were washed with brine (5 mL), dried over MgSO₄and concentrated to give the desired product which was used withoutfurther purification.

tert-butyl (7-formylbenzo[d]thiazol-2-yl)carbamate

tert-butyl (7-(hydroxymethyl)benzo[d]thiazol-2-yl)carbamate (177 mg,0.63 mmol) was dissolved in DCM (5 mL) after which Dess-Martinperiodinane (321 mg, 0.76 mmol) was added at room temperature. After 30minutes the reaction contents were quenched by the addition of saturatedaqueous Na₂SO₃ (3 mL) and stirred vigorously for 5 minutes. The reactionmixture was then poured into saturated aqueous NaHCO₃ (5 mL) andextracted with EtOAc (3×15 mL). The combined organic phase was washedwith brine (5 mL), dried over MgSO₄ and concentrated to give the desiredaldehyde which was used without further purification.

2-methyl-1-oxoisoindoline-4-carbaldehyde

To a solution of 4-bromo-2-methylisoindolin-1-one (200 mg, 0.89 mmol) inTHF (3 mL), n-BuLi (0.78 mL, 1.95 mmol) was added to the solution at−78° C. After 30 minutes, DMF (0.273 mL, 3.57 mmol) was added to thesolution. After 1 hour, the reaction was warmed up. Diluted with EtOAcand washed with brine. The organic layer was dried over sodium sulfate,and concentrated. The product was purified by chromatography on silicagel (eluent: EtOAc/hexanes) to yield the product after lyophilizationfrom water/MeCN.

1-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde

To a solution of 6-chloro-2-methylnicotinaldehyde (1.0 g, 6.43 mmol) inconc. HCl (3 mL), was heated to 90° C. for O.N. Cooled it down andpoured it to ice water (20 mL). Filtered and dried with vacuum. Usedwithout further purification.

To a suspension of 6-oxo-1,6-dihydropyridine-3-carbaldehyde (300 mg,2.19 mmol) in DMF, sodium hydride (96 mg, 2.4 mmol) was added to thesuspension under ice bath condition. Iodomethane (0.15 mL, 2.4 mmol) wasadded to the suspension. Then it was stirred for overnight. Diluted withEtOAc and washed with brine. The organic layer was dried andconcentrated. Used without further purification.

3-methyl-4-oxo-3,4-dihydroquinazoline-8-carbaldehyde

To a suspension of 3,8-dimethylquinazolin-4(3H)-one (300 mg, 2 mmol)(prepared according to Organic and Biomolecular Chemistry, 2011, vol. 9,No. 17 p. 6089-6099) and selenium dioxide (955 mg, 9 mmol) in1,2-dichlorobenzene (1270 mg, 9 mmol) was heated to 170° C. overnight.The organic layer was dried over MgSO₄, filtered, concentrated, andpurified by via silica gel chromatography (eluent: EtOAc/hexanes) toyield the title compound.

Example Amines

(2,2-dimethylpropyl-1,1-d2)amine HCl

LiAlD₄ (252 mg, 6.02 mmol) was suspended in Et₂O (10 mL) at roomtemperature. Trimethylacetonitrile (0.67 mL, 6.02 mmol) was then addedslowly as a solution in Et₂O (6 mL) keeping the temperature belowreflux. After 30 minutes the reaction mixture was quenched by careful,slow addition of water until gas evolution ceased. Saturated aqueousRochelle's salt solution (50 mL) was then added and the resultingsolution stirred vigorously for 2 hours. The phases were then separatedand the aqueous extracted with Et₂O (3×30 mL). The combined organicphases were washed with brine (15 mL), dried over MgSO₄ and filtered. Tothe product solution in ether was added HCl (1.0M in ether, 15 mL, 15mmol) after which the newly formed HCl salt was collected by filtration.

(R)-1-phenylpropan-1-amine-d7

Ellman Auxiliary Condensation:

(S)-(−)-2-methyl-2-propanesulfinamide (862 mg, 7.12 mmol) was dissolvedin DCM (15 mL). PPTS (81 mg, 0.32 mmol), MgSO₄ (3.89 g, 32.3 mmol), andbenzaldehyde-d were then added and the resulting mixture allowed to stirat room temperature for 4 hours. The reaction mixture was filteredthrough celite rinsing with DCM, concentrated and purified by flashchromatography (eluent: EtOAc/hexanes) to give the desired product.

Grignard Formation and Addition to Sulfinimine:

Ethylbromide-d5 (1.00 g, 8.77 mmol) as a solution in dry THF (2 mL) wasadded to a suspension of magnesium turnings (426 mg, 17.5 mmol) in dryTHF (7 mL) and stirred at room temperature for 2 hours. Heat generationand discoloration indicate successful Grignard reagent formation to givean approximately 1.0M solution of EtMgBr-d5 in THF. EtMgBr-d5 (1.0M inTHF, 7.2 mL, 7.2 mmol) was added dropwise to a solution of sulfinimine(752 mg, 3.58 mmol) in DCM (10 mL) at −78° C. After stirring for 3 hoursat −78° C., the reaction mixture was allowed to warm to room temperatureovernight. The reaction contents were quenched by the addition ofsaturated aqueous NH₄Cl (5 mL), poured into water (5 mL) and extractedwith EtOAc (3×30 mL). The combined organic phases were washed with brine(15 mL), dried over MgSO₄ and concentrated. The crude residue waspurified by flash chromatography (eluent: EtOAc/hexanes) to give thedesired product.

Auxilliary Removal:

Starting material (451 mg, 1.84 mmol) was dissolved in MeOH (0.9 mL) atroom temperature. HCl (4.0M in dioxane, 0.92 mL, 3.69 mmol) was addedand the solution stirred for 30 minutes. Reaction mixture was dilutedwith Et₂O (20 mL) and the resulting precipitate collected by filtrationto give the desired product as an HCl salt.

(1R,2R)-2-((S)-amino(phenyl)methyl)cyclopropanecarbonitrile

2-benzoylcyclopropanecarbonitrile

Phenacyl chloride (10.0 g, 64.7 mmol) and DABCO (7.26 g, 64.7 mmol) weredissolved in THF (200 mL) and DMSO (50 mL) at room temperature andstirred for 30 minutes. Na₂CO₃ (10.3 g, 97.0 mmol) and acrylonitrile(8.48 mL, 129.4 mmol) were then added and the resulting mixture heatedto 90° C. overnight. The reaction contents were quenched by the additionof saturated aqueous NH₄Cl (40 mL), poured into water (20 mL) andextracted with EtOAc (3×150 mL). The combined organic phases were washedwith brine (40 mL), dried over MgSO₄ and concentrated. The crude residuewas purified by flash chromatography (eluent: EtOAc/hexanes) to givetrans-2-benzoylcyclopropanecarbonitrile (5.91 g, 53%) andcis-2-benzoylcyclopropanecarbonitrile separately and both as racemicmixtures.

(R)—N-(((1S,2S)-2-cyanocyclopropyl)(phenyl)methylene)-2-methylpropane-2-sulfinamideand(R)—N-(((1R,2R)-2-cyanocyclopropyl)(phenyl)methylene)-2-methylpropane-2-sulfinamide

Racemic trans-2-benzoylcyclopropanecarbonitrile (1.00 g, 5.84 mmol),(R)-(+)-2-methyl-2-propanesulfinamide (2.12 g, 17.5 mmol) andtitanium(IV) ethoxide (7.35 mL, 35.1 mmol) were combined and heated to85° C. for 3 hours. The reaction mixture was cooled to room temperature,diluted with EtOAc (100 mL) followed by water (5 mL) and allowed to stirfor 30 minutes). The white precipitate was removed via filtration andthe filtrate was washed with brine and concentrated. The crude residuewas purified by flash chromatography (eluent: EtOAc/hexanes) to give(R)—N-(((1R,2R)-2-cyanocyclopropyl)(phenyl)methylene)-2-methylpropane-2-sulfinamideand(R)—N-(((1S,2S)-2-cyanocyclopropyl)(phenyl)methylene)-2-methylpropane-2-sulfinamideas pure enantiomers.

(R)—N—((S)-((1R,2R)-2-cyanocyclopropyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide

(R)—N-(((1R,2R)-2-cyanocyclopropyl)(phenyl)methylene)-2-methylpropane-2-sulfinamide(250 mg, 0.91 mmol) was dissolved in THF and brought to −78° C. NaBH₄(70.0 mg, 1.85 mmol) was added as a single portion and the reactionmixture allowed to warm slowly to room temperature. Upon reaching roomtemperature the reaction contents were quenched with water (2 mL) andextracted with EtOAc (3×8 mL). The combined organic phases were washedwith brine (5 mL), dried over MgSO₄ and concentrated. The crude residuewas purified by flash chromatography (eluent: EtOAc/hexanes) to give(R)—N—((R)-((1R,2R)-2-cyanocyclopropyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(56 mg, 22%) and(R)—N—((S)-((1R,2R)-2-cyanocyclopropyl)(phenyl)methyl)-2-methylpropane-2-sulfinamideas pure enantiomers.

(1R,2R)-2-((S)-amino(phenyl)methyl)cyclopropanecarbonitrile

(R)—N—((S)-((1R,2R)-2-cyanocyclopropyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(143 mg, 0.52 mmol) was dissolved in MeOH (0.5 mL) at room temperature.HCl (4.0M in dioxane, 0.26 mL, 1.04 mmol) was added and the solutionstirred for 30 minutes. Reaction mixture was diluted with Et₂O (20 mL)and the resulting precipitate collected by filtration to give thedesired product as an HCl salt.

3-chloro-2-cyclopropoxyaniline

1-chloro-2-cyclopropoxy-3-nitrobenzene

To a solution of NaH (60% dispersion in mineral oil, 319 mg, 7.98 mmol)in THF (10 mL) was slowly added cyclopropyl alcohol (0.35 mL, 5.58mmol). After 15 minutes of stirring, 1-chloro-2-fluoro-3-nitrobenzene(700 mg, 3.99 mmol) was added and the resulting solution heated to 75°C. for 1 hour. The reaction mixture was cooled to room temperature,quenched with water (5 mL) and extracted with EtOAc (3×15 mL). Thecombined organic phases were washed with brine (5 mL), dried over MgSO₄and concentrated. The crude residue was purified by flash chromatography(eluent: EtOAc/hexanes) to give the desired product.

3-chloro-2-cyclopropoxyaniline

1-chloro-2-cyclopropoxy-3-nitrobenzene (420 mg, 1.97 mmol) was dissolvedin EtOH (8 mL) at room temperature. Iron (549 mg, 9.83 mmol), CaCl₂ (327mg, 2.95 mmol) and water (1 mL) were then added and the resultingmixture heated to 75° C. for 3 hours. The solids were removed byfiltration washing with MeOH and EtOAc, the filtrate concentrated, andthen redissolved in EtOAc (100 mL). The organic phase was washed withsaturated aqueous NaHCO₃ (2×20 mL), brine (20 mL), dried over MgSO₄ andconcentrated to give the product which was used without furtherpurification.

Diazotransfer Reaction and Generation of Azides

3-(Aminomethyl)oxetan-3-ol (50 mg, 0.49 mmol) was added to a suspensionof 1H-imidazole-1-sulfonyl azide hydrochloride (129.5 mg, 0.62 mmol),potassium carbonate (136 mg, 0.99 mmol), and copper (II) sulfatepentahydrate (12.3 mg, 0.049 mmol) in methanol (1.0 mL). The bluemixture was stirred at room temperature for 16 hrs and was used withoutworkup in the Click chemistry (Example 4). Reference: E. D. Goddard, et.al., Org. Lett., 2007, p. 3797.

Piperidine-Triazole Aldehyde

Benzyl 4-(tosyloxy)piperidine-1-carboxylate (2)

Benzyl 4-hydroxypiperidine-1-carboxylate (1) (17.2 g, 73.1 mmol) andp-toluenesulfonyl chloride (15.3 g, 80.4 mmol) were dissolved inpyridine (50 mL) and stirred at room temperature. After 23 hrs, thepyridine was removed under reduced pressure and the residue wasdissolved in EtOAc (300 mL). The organic phase was washed with water(2×150 mL) and saturated ammonium chloride (100 mL), dried over sodiumsulfate and the solvent was removed under reduced pressure. The residuewas subjected to flash chromatography (eluent: ethyl acetate/hexanes).The fractions containing product were combined and the solvent wasremoved under reduced pressure, providing benzyl4-(tosyloxy)piperidine-1-carboxylate (2).

Benzyl 4-azidopiperidine-1-carboxylate (3)

Sodium azide (2.48 g, 38.2 mmol) was added to a solution of benzyl4-(tosyloxy)piperidine-1-carboxylate (2) (12.4 g, 31.8 mmol) indimethylformamide (100 mL). The mixture was heated at 90° C. for 30minutes. The mixture was cooled and diluted with ethyl acetate (250 mL)and washed with water (2×15 mL), 5% aqueous lithium chloride (10 mL) andbrine (10 mL). The organic phase was dried over sodium sulfate andconcentrated (NOT to dryness) providing the desired material. Allmaterial was used in the next step.

Benzyl4-(4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (4)

Copper powder (2.0 g, 31.5 mmol), was added to a solution of benzyl4-azidopiperidine-1-carboxylate (3) (8.2 g, 31.5 mmol)3,3-diethoxyprop-1-yne (4.44 g, 34.6 mmol) and saturated copper (II)sulfate (8 mL) in tetrahydrofuran (100 mL). After 17 hrs, the mixturewas filtered through a pad of celite. The solvent was removed underreduced pressure and the residue was taken up in ethyl acetate (200 mL).The organic phase was washed with brine (3×100 mL), dried over sodiumsulfate and concentrated. The residue was subjected to flashchromatography on silica gel (eluent: ethyl acetate/hexanes). Thefractions containing product were combined and the solvent was removedunder reduced pressure providing benzyl4-(4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate(4).

Benzyl 4-(4-formyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (5)

Aqueous hydrochloric acid (1 M, 2.2 mL, 2.2 mmol) was added to asolution of benzyl4-(4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (4)(429 mg, 1.1 mmol) in tetrahydrofuran (4 mL) and water (2 mL). Theorganic solvent was removed under reduced pressure. The aqueous mixturewas diluted with acetonitrile (2 mL) and subjected to lyophilization.

tert-butyl 3-formyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate

N,N-Diisopropylethylamine (1.53 mL, 8.82 mmol) was added to a solutionof6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylicacid (1.00 g, 3.53 mmol) andN-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (1.62 g, 4.24 mmol) in dimethylformamide (15mL). After 2 min N,O-Dimetylhydroxylamine hydrochloride (413 mg, 4.24mmol) was added. After 16 h the reaction was diluted with ethyl acetate(75 mL) and washed with water (2×25 mL), saturated ammonium chloride(2×25 mL) and brine (25 mL). The organic phase was dried over sodiumsulfate and the solvent was removed under reduced pressure. The residuewas subjected to flash chromatography (0-100% ethyl acetate/hexanes).The fractions containing product were combined and the solvent wasremoved under reduced pressure, providing tert-butyl3-(methoxy(methyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate.

A solution of diisobutylaluminum hydride in tetrahydrofuran (4.42 mL,1.0 M, 4.42 mmol) was added dropwise to a solution of tert-butyl3-(methoxy(methyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate(1.03 g, 3.15 mmol) in tetrahydrofuran (20 mL) at −78° C. under anatmosphere of argon. After 5 h at −78° C. the reaction was 40% complete.A solution of diisobutylaluminum hydride in tetrahydrofuran (3.15 mL,1.0 M, 3.15 mmol was added dropwise. After 30 min the reaction wasquenched with saturated ammonium chloride (20 mL) at −78° C. and allowedto warm to room temperature. The organic phase was shaken with water (20mL) and ethyl acetate (75 mL) (causing a gel to form). Hydrochloric acid(2 N, 5 mL) was added and the solid was removed by filtration through apad of celite. The organic phase was washed with saturated sodiumbicarbonate (25 mL) and brine (25 mL). The organic phase was dried oversodium sulfate and concentrated. The residue was subjected to flashchromatography (0-50% ethyl acetate/hexanes). The fractions containingproduct were combined and the solvent was removed under reducedpressure, providing tert-butyl3-formyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate.

Compound Examples Example 1 Procedure 1

8-chloro-4-(neopentylamino)-6-nitroquinoline-3-carbonitrile:4,8-dichloro-6-nitroquinoline-3-carbonitrile (615 mg, 2.29 mmol),neopentylamine (220 mg, 0.25 mmol) and triethylamine (278 mg, 2.75 mmol)in iso-propanol (4 mL) were heated under microwave conditions at 150° C.for 45 minutes. The reaction was cooled to room temperature. Water wasadded and the resulting precipitate was collected via filtration. Thecrude product was used in the next step without further purification.

ES/MS 319.1 (M+H⁺).

Alternative Reaction Conditions for this Transformation:

4,8-dichloro-6-nitroquinoline-3-carbonitrile (3000 mg, 11.2 mmol),neopentylamine (1073 mg, 12.3 mmol) and triethylamine (1246 mg, 12.3mmol) in iso-propanol (60 mL) were heated at 80° C. for 4 hrs. Thereaction was cooled to room temperature. Removed the solvents andpurified the crude reaction product via chromatography on silica gel(eluent: EtOAc/hexanes) yielding the product.

ES/MS (M+H⁺) 319.1.

6-amino-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile

8-chloro-4-(neopentylamino)-6-nitroquinoline-3-carbonitrile (699 mg, 2.2mmol), calcium chloride (483.6 mg, 3.28 mmol), iron powder (612.3 mg,10.96 mmol) were heated in ethanol (22 mL)/water (2.2 mL) at 60° C. for1 hour. The reaction was cooled to room temperature and solids wereremoved via filtration. The solids were washed with EtOAc and thecombined organic layers were washed with aqueous sodium bicarbonatesolution, brine, and were dried over sodium sulfate. Filtration andevaporation of all volatiles yielded the product.

ES/MS 289.1 (M+H⁺).

Alternative Reduction Conditions with Tin Chloride:

8-chloro-4-(neopentylamino)-6-nitroquinoline-3-carbonitrile (2,000 mg,6.2 mmol) and tin chloride (7079 mg, 31.3 mmol) heated at 70° C. for 4h. More tin chloride (2832 mg, 12.6 mmol) was added. After 5 hrs, thereaction was complete. The reaction was cooled to room temperature. Halfof the ethanol was removed under reduced pressure. The mixture was addedto NaHCO₃ (200 mL) and diluted with EtOAc (500 mL). The organic phasewas washed with brine (200 mL) and dried over sodium sulfate. Thesolvent was removed under reduced pressure, providing the desiredmaterial.

1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.32 (d, J=2.1 Hz, 1H), 7.29(t, J=7.3 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 5.74 (s, 2H), 3.66 (d, J=6.6Hz, 2H), 0.96 (s, 9H).

ES/MS 289.1 (M+H⁺).

(S)-8-chloro-6-(((1-cyclopropyl-1H-1,2,3-triazol-4-yl)(4-fluoro-3-pyridyl)methyl-d)amino)-4-(neopentylamino)quinoline-3-carbonitrile

6-amino-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile (75 mg, 0.26mmol), CuI (3.6 mg, 0.019 mmol) and2,6-bis((4S,5R)-4,5-diphenyl-4,5-dihydrooxazol-2-yl)pyridine [oxazolineligand] (9.9 mg, 0.019 mmol) were sonicated in MeOH (3.5 mL) for ˜1minute. Alkynyl acetate (44.4 mg, 0.23 mmol) and di-isopropyl ethylamine (29.4 mg, 0.229 mmol) were added and the reaction was stirred atroom temperature overnight. Tert-butyl azide (45 mg, 0.454 mmol) wasadded and the reaction was stirred or additional 24 hrs at roomtemperature. Solvents were removed in vacuo and the crude material waspurified via RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the productas trifluoro acetate salt.

1H NMR (400 MHz, DMSO-d6) δ 8.37 (m, 2H), 8.17 (s, 1H), 8.05 (m, 1H),7.79 (brs, 1H), 7.62 (d, J=2.2 Hz, 1H), 7.51 (br s, 1H), 7.15 (m, 2H),4.03 (m, 1H), 3.44 (dd, J=13.9/5.5 Hz, 1H), 1.59 (s, 9H), 0.88 (s, 9H).

ES/MS 522.2 (M+H⁺).

Example 2 Procedure 28-chloro-6-(((S)-(1-isopropyl-1H-1,2,3-triazol-4-yl)(2-methylpyridin-3-yl)methyl)amino)-4-(((R)-1-phenylpropyl)amino)quinoline-3-carbonitrile

(R)-8-chloro-6-nitro-4-((1-phenylpropyl)amino)quinoline-3-carbonitrile

4,8-dichloro-6-nitroquinoline-3-carbonitrile (200 mg, 0.75 mmol),(R)-ethyl benzylamine (121 mg, 0.895 mmol) in iso-propanol (3 mL) wereheated under microwave conditions at 150° C. for 45 minutes. Thereaction was cooled to room temperature. Water and EtOAc were added. Theaqueous layer was extracted with EtOAc and the combined organic layerswere dried over sodium sulfate. Filtration and evaporation of solventsyielded the crude product which was used in the next step withoutfurther purification.

ES/MS 367.1 (M+H⁺).

6-amino-8-chloro-4-((1-phenylpropyl)amino)quinoline-3-carbonitrile

(R)-6-amino-8-chloro-4-((1-phenylpropyl)amino)quinoline-3-carbonitrile(287 mg, 0.78 mmol), calcium chloride (172.6 mg, 1.17 mmol), iron powder(218.5 mg, 3.91 mmol) were heated in ethanol (5 mL)/water (0.5 mL) at60° C. for 1 hour. The reaction was cooled to room temperature andsolids were removed via filtration. The solids were washed with EtOAcand the combined organic layers were washed with aqueous sodiumbicarbonate solution, brine, and were dried over sodium sulfate.Filtration and evaporation of all volatiles yielded the product.

ES/MS 337.1 (M+H⁺).

8-chloro-6-(((R)-1-(2-methylpyridin-3-yl)prop-2-yn-1-yl)amino)-4-(((R)-1-phenylethyl)amino)quinoline-3-carbonitrile

CuI (2.0 mg, 0.01 mmol) and2,6-bis((4S,5R)-4,5-diphenyl-4,5-dihydrooxazol-2-yl)pyridine [oxazolineligand] (6.9 mg, 0.013 mmol) were sonicated in MeOH (3.0 mL) for ˜5minutes. 1-(2-methylpyridin-3-yl)prop-2-yn-1-yl acetate (50 mg, 0.27mmol) in MeOH (1 mL),(R)-6-amino-8-chloro-4-((1-phenylpropyl)amino)quinoline-3-carbonitrile(75 mg, 0.223 mmol), and di-isopropyl ethyl amine (34 mg, 0.27 mmol)were added and the reaction was stirred at room temperature overnight.The crude reaction product was purified by silica gel chromatography(20%-100% EtOAc in hexanes) to provide the product.

ES/MS 465.99 (M+H⁺).

8-chloro-6-(((S)-(1-isopropyl-1H-1,2,3-triazol-4-yl)(2-methylpyridin-3-yl)methyl)amino)-4-(((R)-1-phenylpropyl)amino)quinoline-3-carbonitrile

8-chloro-6-(((R)-1-(2-methylpyridin-3-yl)prop-2-yn-1-yl)amino)-4-(((R)-1-phenylethyl)amino)quinoline-3-carbonitrile(45 mg, 0.10 mmol) was dissolved in THF (0.5 mL) at room temperature andcopper (I) thiophene carboxylate (5.7 mg, 0.030 mmol) was added.2-azidopropane (10 mg, 0.120 mmol) was added and the reaction wasstirred for 4 hours at room temperature. The reaction was partitionedbetween aqueous sodium bicarbonate solution and EtOAc. The aqueous layerwas extracted with EtOAc and the combined layers were washed withsaturated sodium bicarbonate solution and dried over sodium sulfate.Filtration and evaporation of solvents gives crude material. The crudematerial was purified RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield theproduct as trifluoroacetate salt.

¹H NMR (400 MHz, CD₃OD) δ 8.61 (m, 1H), 8.37 (m, 1H), 8.29 (m, 1H), 8.05(m, 1H), 7.73 (m, 1H), 7.60 (s, 1H), 7.32 (m, 5H), 7.14 (m, 1H), 6.46(s, 1H), 5.64 (m, 1H), 4.88 (m, 1H), 2.83 (s, 3H), 2.17-2.02 (m, 2H),1.56 (d, 6H), 0.97 (m, 3H).

ES/MS 551.09 (M+H⁺).

Example 3 Procedure 38-chloro-6-(((S)-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)(2,6-difluoropyridin-3-yl)methyl-d))amino-4-(((R)-1-phenylpropyl)amino)quinoline-3-carbonitrile

8-chloro-6-(((S)-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)(2,6-difluoropyridin-3-yl)methyl-d))amino)-4-(((R)-1-phenylpropyl)amino)quinoline-3-carbonitrile

CuI (2.0 mg, 0.01 mmol) and2,6-bis((4S,5R)-4,5-diphenyl-4,5-dihydrooxazol-2-yl)pyridine [oxazolineligand] (4.6 mg, 0.009 mmol) were sonicated in MeOH (3.0 mL) for ˜5minutes. alkynyl acetate (79 mg, 0.37 mmol) in MeOH (1 mL),(R)-6-amino-8-chloro-4-((1-phenylpropyl)amino)quinoline-3-carbonitrile(50 mg, 0.148 mmol), and di-isopropyl ethyl amine (23 mg, 0.18 mmol)were added and the reaction was stirred at room temperature overnight.The crude reaction mixture was used directly for the next step.

ES/MS: 489.19 (M+H⁺).

To the reaction mixture was added cyclopropylazide (16 mg, 0.192 mmol).After 1 hour at room temperature, the mixture was filtered and thenpurified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the productas trifluoroacetate salt.

¹H NMR (400 MHz, CD₃OD) δ 8.43 (m, 1H), 8.05 (m, 1H), 8.01 (m, 1H), 7.64(m, 1H), 7.42-7.25 (m, 6H), 6.98 (m, 1H), 5.80-5.66 (m, 1H), 3.97-3.84(m, 1H), 2.25-2.01 (m, 2H), 1.28-1.11 (m, 4H), 1.01 (m, 3H).

ES/MS: 572.24 (M+H⁺).

Example 4 Procedure 4

8-chloro-6-(((S)-(1-((3-hydroxyoxetan-3-yl)methyl)-1H-1,2,3-triazol-4-yl)(pyridin-3-yl)methyl)amino)-4-(((R)-1-phenylpropyl)amino)quinoline-3-carbonitrile

8-chloro-4-(((R)-1-phenylpropyl)amino)-6-(((R)-1-(pyridin-3-yl)prop-2-yn-1-yl)amino)quinoline-3-carbonitrile(20 mg, 0.046 mmol), copper powder (15 mg, 0.23 mmol), acetic acid (118uL, 1.8 mmol) and saturated aqueous copper (II) sulfate (0.1 mL) and THF(3 mL) were added to the stock solution of 3-(azidomethyl)oxetan-3-ol(0.049 mmol). After 2 hrs, the reaction was complete and volatiles wereremoved in vacuo. The crude was partitioned between ethyl acetate (15mL) and water. The organic layer was washed with saturated sodiumbicarbonate, brine, dried over Na₂SO₄ and concentrated after filtration.The residue was taken up in water (1 mL) and MeOH (1 mL) with 2 drops ofTFA and subjected to RP-HPLC (eluent: water/MeCN*0.1% TFA). Thefractions containing the desired product were combined and subjected tolyophilization, providing the desired compound.

1H NMR (400 MHz, DMSO-d6) δ 8.84 (dd, J=14.0, 2.2 Hz, 1H), 8.64-8.52 (m,1H), 8.23 (d, J=2.1 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.05 (d, J=6.7 Hz,1H), 7.65-7.54 (m, 2H), 7.46 (d, J=9.5 Hz, 1H), 7.43-7.38 (m, 1H),7.38-7.31 (m, 2H), 7.28-7.21 (m, 2H), 7.21-7.15 (m, 3H), 6.48 (d, J=6.9Hz, 1H), 5.48 (q, J=7.7 Hz, 1H), 4.68 (d, J=2.0 Hz, 2H), 4.50 (dd,J=6.2, 4.5 Hz, 3H), 4.41 (dd, J=6.7, 3.4 Hz, 2H), 2.12 (dt, J=14.5, 7.4Hz, 1H), 2.04-1.78 (m, 1H), 0.94 (t, J=7.3 Hz, 3H).

ES/MS 581.2 (M+H⁺). Example 5 procedure 5

(R)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)-6-((1-(2,5-dichlorothiophen-3-yl)prop-2-yn-1-yl)amino)quinoline-3-carbonitrile

CuI (4.1 mg, 0.022 mmol) and2,6-bis((4S,5R)-4,5-diphenyl-4,5-dihydrooxazol-2-yl)pyridine [oxazolineligand] (13.5 mg, 0.026 mmol) were sonicated in MeOH (1 mL) for ˜5minutes. Additional MeOH (4 mL) was added. Alkynyl acetate (150.7 mg,0.61 mmol),6-amino-8-chloro-4-((4-chloro-3-fluorophenyl)amino)quinoline-3-carbonitrile(150 mg, 0.43 mmol), and di-isopropyl ethyl amine (67 mg, 0.52 mmol)were added and the reaction was stirred at −15 OC for 4 days. Thesolvents were removed in vacuo. The crude reaction product was purifiedvia silica gel chromatography (eluent: EtOAc/hexanes) to yield theproduct.

1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.45 (s, 1H), 7.54 (dd, J=6.4,2.4 Hz, 2H), 7.43 (t, J=9.0 Hz, 1H), 7.38 (d, J=2.3 Hz, 1H), 7.30 (d,J=4.3 Hz, 1H), 7.27 (s, 1H), 7.11 (d, J=8.6 Hz, 1H), 5.54 (dd, J=8.6,2.2 Hz, 1H), 3.51 (d, J=2.2 Hz, 1H).

ES/MS 534.9 (M+H⁺).

(S)-tert-butyl4-(4-(((8-chloro-4-((3-chloro-4-fluorophenyl)amino)-3-cyanoquinolin-6-yl)amino)(2,5-dichlorothiophen-3-yl)methyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

(R)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)-6-((1-(2,5-dichlorothiophen-3-yl)prop-2-yn-1-yl)amino)quinoline-3-carbonitrile(174 mg, 0.324 mmol) and N-Boc piperidine 4 azide (73.4 mg, 0.324 mmol)were dissolved in THF (5 mL). Copper thiophenecarboxylate (6.2 mg, 0.032mmol) was added and the reaction was stirred at room temperature for 16hrs. The volatiles were removed under reduced pressure and the residuewas purified by chromatography on silica gel (eluent: EtOAc/hexanes).The fractions containing product were combined and the solvent wasremoved under reduced pressure, providing the product.

1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.47 (s, 1H), 8.16 (s, 1H),7.60 (d, J=2.2 Hz, 1H), 7.40-7.33 (m, 2H), 7.27 (d, J=8.3 Hz, 1H), 7.14(dd, J=7.1, 2.0 Hz, 2H), 7.10 (s, 1H), 5.96 (d, J=8.2 Hz, 1H), 4.72-4.59(m, 1H), 4.01 (q, J=9.1, 8.1 Hz, 3H), 2.86 (d, J=17.5 Hz, 2H), 1.96 (d,J=5.0 Hz, 3H), 1.77 (qd, J=12.2, 4.4 Hz, 2H), 1.39 (s, 9H).

ES/MS 762.9 (M+H⁺).

Alternatively, the cycloaddition can be performed in a one-pot fashionusing the Cu(I) present from the N-alkylation.

(S)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)-6-(((2,5-dichlorothiophen-3-yl)(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)amino)quinoline-3-carbonitrile

(S)-tert-butyl4-(4-(((8-chloro-4-((3-chloro-4-fluorophenyl)amino)-3-cyanoquinolin-6-yl)amino)(2,5-dichlorothiophen-3-yl)methyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate(157 mg, 0.206 mmol) was suspended in DCM (0.5 mL). HCl in dioxane (5mL; 4M) was added and the reaction was stirred at room temperature for30 minutes. The solvents were removed under reduced pressure. Theresidue was subjected to flash chromatography (eluent: (20% MeOH inEtOAc)/hexanes). The fractions containing product were combined and thesolvent was removed under reduced pressure. The residue was taken up inEtOAc/aqueous saturated sodium bicarbonate solution. The organic layerwas isolated and dried over sodium sulfate. Filtration and evaporationof the solvent in vacuo gave the product.

1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.45 (s, 1H), 8.10 (s, 1H),7.59 (d, J=2.1 Hz, 1H), 7.37 (t, J=8.9 Hz, 2H), 7.26 (d, J=8.1 Hz, 1H),7.13 (d, J=10.0 Hz, 3H), 5.96 (d, J=8.2 Hz, 1H), 4.48 (tt, J=11.8, 4.3Hz, 1H), 3.75-3.62 (m, 1H), 3.55 (s, 1H), 3.46 (dq, J=9.7, 5.2 Hz, 1H),2.99 (d, J=12.2 Hz, 2H), 2.55 (td, J=12.5, 2.4 Hz, 2H), 1.92 (dd,J=11.9, 3.7 Hz, 2H), 1.75 (t, J=12.0 Hz, 3H).

ES/MS 662.1 (M+H⁺).

(S)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)-6-(((2,5-dichlorothiophen-3-yl)(1-(1-ethylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)amino)quinoline-3-carbonitrile

(S)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)-6-(((2,5-dichlorothiophen-3-yl)(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)amino)quinoline-3-carbonitrile(138 mg, 0.208 mmol) was dissolved in THF (3 mL) and dichloro ethane (3mL). Acetaldehyde (91.8 mg, 2.08 mmol) and sodium triacetoxy borohydride(176 mg, 0.833 mmol) were added and the reaction was stirred at roomtemperature for 1 hr. The reaction was diluted with EtOAc and washedwith aqueous sodium bicarbonate solution, brine, and was dried oversodium sulfate. The crude material was filtered and the volatiles wereremoved in vacuo and the crude was purified via chromatography on silicaget (eluent: MeOH (20%) in EtOAc/hexanes) to yield the product.

1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H),7.60 (d, J=2.3 Hz, 1H), 7.41-7.34 (m, 2H), 7.27 (d, J=8.2 Hz, 1H), 7.15(dd, J=9.1, 3.3 Hz, 2H), 7.12 (s, 1H), 5.96 (d, J=8.1 Hz, 1H), 4.50-4.32(m, 1H), 3.00-2.83 (m, 2H), 2.42-2.25 (m, 2H), 2.18-1.81 (m, 6H), 0.98(t, J=7.2 Hz, 3H).

ES/MS 689.9 (M+H⁺).

Example 6 Procedure 6

Benzyl4-(4-(((8-chloro-4-((3-chloro-4-fluorophenyl)amino)-3-cyanoquinolin-6-yl)amino)(3-pyridyl)methyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

A suspension of the6-amino-8-chloro-4-((4-chloro-3-fluorophenyl)amino)quinoline-3-carbonitrile(159 mg, 0.51 mmol), aldehyde (176 mg, 0.51 mmol) and pTSA (9.6 mg, 0.05mmol) in toluene (12 mL) was heated at reflux (50 mL RBF equipped with aHickman still). After 4 hrs, the solvent was removed under reducedpressure. The solid was dissolved in methyl-THF and 3-pyridylmagnesiumbromide (2.03 mmol; 8.1 mL 0.25-M Me-THF) was added dropwise at −10 C.After 130 min, the reaction was quenched with sat NH₄Cl (3 mL). Thelayers were separated and the aqueous phase was extracted with EtOAc (15mL). The combined organic layers were washed with brine (5 mL), driedover sodium sulfate and concentrated. The residue was subjected to flashchromatography on silica gel (eluent: EtOAc/hexanes). The fractionscontaining product were combined and the solvent was removed providingthe product.

8-chloro-4-((3-chloro-4-fluorophenyl)amino)-6-(((1-(1-ethylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)(pyridin-3-yl)methyl)amino)quinoline-3-carbonitrile

Benzyl4-(4-(((8-chloro-4-((3-chloro-4-fluorophenyl)amino)-3-cyanoquinolin-6-yl)amino)(pyridin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate(57 mg, 0.079 mmol) Acetaldehyde (34.7 mg, 0.79 mmol) and Pd—C(25 mg,10%) in EtOH (3 mL)/EtOAc (2 mL) were stirred under an atmosphere ofhydrogen. After 43 hrs, the reaction was filtered and the volatiles wereremoved in vacuo and the crude was purified via RP-HPLC (eluent:water/MeCN 0.1% TFA) to yield the product as trifluoro acetate salt.

¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 1H), 8.74 (d, J=2.2 Hz, 1H), 8.54(dd, J=5.0, 1.5 Hz, 1H), 8.41 (s, 1H), 8.13 (s, 1H), 8.00 (d, J=8.0 Hz,1H), 7.67 (d, J=2.2 Hz, 1H), 7.49 (tt, J=6.8, 3.7 Hz, 3H), 7.42 (t,J=9.0 Hz, 1H), 7.26 (d, J=2.5 Hz, 1H), 7.25-7.21 (m, 1H), 6.20 (d, J=7.8Hz, 2H), 4.79-4.69 (m, 1H), 3.61 (d, J=12.4 Hz, 2H), 3.26-2.98 (m, 4H),2.34 (d, J=13.9 Hz, 2H), 2.15 (q, J=12.5, 11.6 Hz, 2H), 1.22 (t, J=7.3Hz, 3H).

ES/MS: 616.1 (M+H⁺).

Compounds of this sequence can be separated into the respectivestereoisomers via appropriate means (eg. chromatography with chiralstationary phase, crystallography) after the C6 N-alkylation has beenperformed.

Removal of the protecting group in the absence of a reaction partneryields the corresponding un-alkylated amine derivatives.

Example 7 Procedure 7

8-chloro-4-((3-chloro-4-fluorophenyl)amino)-6-((pyridin-2-yl(pyridin-3-yl)methyl)amino)quinoline-3-carbonitrile

To a suspension of the6-amino-8-chloro-4-((4-chloro-3-fluorophenyl)amino)quinoline-3-carbonitrile(50 mg, 0.144 mmol) and pyridin-2-yl(pyridin-3-yl)methanone (27 mg,0.144 mmol) in DCM (1 mL) was added triethylamine (35 mg, 0.346 mmol)followed by TiCl₄ in DCM (0.086 mmol/0.086 mL). The reaction was stirredovernight at room temperature. It was diluted with MeOH (2 mL) andsodium borohydride (16 mg, 0.432 mmol) was added. The reaction wasstirred for 2 hours, then was diluted with water and treated with 1MNaOH until a pH of ˜13 was reached. Solids were removed via filtrationand washed with DCM. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated. The product was purified bychromatography on silica gel (eluent: EtOAc/hexanes) to yield theproduct after lyophilization from water/MeCN.

1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.66 (dd, J=2.4, 0.8 Hz, 1H),8.56 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 8.47-8.39 (m, 2H), 7.87-7.75 (m,3H), 7.61-7.19 (m, 8H), 6.08 (d, J=8.7 Hz, 1H).

ES/MS: 515.1 (M+H⁺).

Example 8 Procedure 8

8-chloro-4-((5,6-difluoropyridin-3-yl)amino)-6-nitroquinoline-3-carbonitrile

4,8-dichloro-6-nitroquinoline-3-carbonitrile (1.4 g, 5.22 mmol),2,6-difluoropyridin-3-amine (755 mg, 5.74 mmol) and pyridinehydrochloride (1.8 g, 15.6 mmol) in iso-propanol (40 mL) was heated at70° C. overnight. The reaction was cooled to room temperature. Water wasadded and the resulting precipitate was collected via filtration. Thecrude product was used in the next step without further purification.ES/MS 362.0 (M+H⁺).

6-amino-8-chloro-4-((5,6-difluoropyridin-3-yl)amino)quinoline-3-carbonitrile

Made from8-chloro-4-((5,6-difluoropyridin-3-yl)amino)-6-nitroquinoline-3-carbonitrilevia step-2 of general procedure 1. ES/MS 332.0 (M+H⁺).

(S)-8-chloro-4-((5,6-difluoropyridin-3-yl)amino)-6-(((1-isopropyl-1H-1,2,3-triazol-4-yl)(pyridin-3-yl)methyl)amino)quinoline-3-carbonitrile)

Made from6-amino-8-chloro-4-((5,6-difluoropyridin-3-yl)amino)quinoline-3-carbonitrileby step-3 of general procedure 1. ES/MS 532.1 (M+H⁺).

Example 9 Procedure 9

(S)-6-((benzo[d]thiazol-7-yl(1-cyclopropyl-1H-1,2,3-triazol-4-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrile( )

DMF (2 mL) was added to(S)-6-((benzo[d]thiazol-7-yl(1-cyclopropyl-1H-1,2,3-triazol-4-yl)methyl)amino)-8-bromo-4-(neopentylamino)quinoline-3-carbonitrile(38 mg, 0.064 mmol) and CuCN (41 mg, 0.46 mmol) in a microwave vial. Thevial was heated to 200° C. for 15 minutes in a microwave and allowed tocool to room temperature. The reaction mixture was poured into water (4mL) and extracted with EtOAc (3×8 mL). The combined organic phases werewashed with brine (5 mL), dried over MgSO₄ and concentrated. The cruderesidue was purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yieldthe product as trifluoro acetate salt. ¹H NMR (400 MHz, Methanol-d₄) δ9.20 (s, 1H), 8.34 (s, 1H), 8.05 (dd, J=7.3, 1.9 Hz, 1H), 7.86 (d, J=2.5Hz, 1H), 7.82 (s, 1H), 7.64-7.54 (m, 2H), 7.16 (d, J=2.6 Hz, 1H), 6.34(s, 1H), 3.97 (d, J=13.7 Hz, 1H), 3.91-3.80 (m, 1H), 3.49 (d, J=13.7 Hz,1H), 1.23-1.07 (m, 4H), 0.81 (s, 9H). ES/MS 534.1 (M+H⁺).

Alternative Introduction of the 8 Cyano Group

6-amino-4-(neopentylamino)quinoline-3,8-dicarbonitrile

Solid Zn(CN)₂ (211 mg, 1.8 mmol) and Pd(PPh)₄ (35 mg, 0.03 mmol) wereadded to a solution of6-amino-8-bromo-4-(neopentylamino)quinoline-3-carbonitrile (500 mg, 1.5mmol) in NMP (20 mL). The resulting mixture was degased by bubblingargon gas through for 5 min. The reaction vessel was sealed then heatedto 120° C. for 16 h. The reaction mixture was cooled then loadeddirectly to silica column to afford the pure nitrile. ES/MS 280.3(M+H⁺).

Further elaboration to final compound according to procedures outlinedin this document

Example 10 Procedure 10

(S)-6-((benzo[d]thiazol-6-yl(1H-1,2,3-triazol-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile

(R)-6-((1-(benzo[d]thiazol-6-yl)prop-2-yn-1-yl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile(40.0 mg, 0.077 mmol) was dissolved in THF (2 mL).Cu(I)-thiophene-2-carboxylate (4.4 mg, 0.023 mmol) and azidomethyloxypivalate (0.018 mL, 0.12 mmol) were added and the resulting solutionstirred at room temperature for 30 minutes. The reaction contents werepoured into saturated aqueous NaHCO₃ solution (5 mL) and extracted withEtOAc (3×8 mL). The combined organic layers were washed with brine (5mL), dried over MgSO₄ and concentrated. The resulting crude residue wasthen dissolved in MeOH (2 mL). NaOH (1.0M in water, 0.17 mL, 0.17 mmol)was added and the reaction allowed to stir at room temperature for 30min. HCl (1.0M in water, 0.17 mL, 0.17 mmol) was then added, theresulting solution poured into water (5 mL) and extracted with EtOAc(3×8 mL). The combined organic layers were washed with brine (5 mL),dried over MgSO₄ and concentrated. The resulting crude residue waspurified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the productas trifluoro acetate salt.

ES/MS 561.0 (M+H⁺).

Example 11 Procedure 118-chloro-6-[[(S)-(1-cyclopropyltriazol-4-yl)-deuterio-(6-fluoropyridin-3-yl)methyl]amino]-4-[[(1R)-3-fluoro-1-phenylpropyl]amino]quinoline-3-carbonitrile

(R)-8-chloro-4-((3-hydroxy-1-phenylpropyl)amino)-6-nitroquinoline-3-carbonitrile

4,8-dichloro-6-nitroquinoline-3-carbonitrile (400 mg, 1.49 mmol),(R)-3-amino-3-phenylpropan-1-ol (270.76 mg, 1.79 mmol) in iso-propanol(1.5 mL) were heated under microwave conditions at 150° C. for 45minutes. The reaction was cooled to room temperature. Water and Et₂Owere added. The aqueous layer was extracted with Et₂O and the combinedorganic layers were dried over sodium sulfate. Filtration andevaporation of solvents yielded the crude product which was used in thenext step without further purification.

ES/MS 383.1 (M+H⁺).

(R)-8-chloro-4-((3-fluoro-1-phenylpropyl)amino)-6-nitroquinoline-3-carbonitrile

(R)-8-chloro-4-((3-hydroxy-1-phenylpropyl)amino)-6-nitroquinoline-3-carbonitrile(100 mg, 0.26 mmol) was treated with Deoxofluor® (0.6 mL) at roomtemperature for 16 hours. The reaction mixture was cooled in an ice bathand carefully quenched with saturated sodium bicarbonate solution, thenextracted with ethyl acetate. The organic phase was dried over sodiumsulfate, filtered and concentrated to give the crude product (115 mg)which was used without further purification.

ES/MS 385.1 (M+H⁺).

(R)-6-amino-8-chloro-4-((3-fluoro-1-phenylpropyl)amino)quinoline-3-carbonitrile

(R)-8-chloro-4-((3-fluoro-1-phenylpropyl)amino)-6-nitroquinoline-3-carbonitrile(115 mg, 0.3 mmol), Calcium chloride dihydrate (66 mg, 0.45 mmol), andiron powder (83 mg, 1.49 mmol) were heated in ethanol (3 mL)/water (0.3mL) at 60° C. for 12 hours. The reaction was cooled to room temperatureand solids were removed via filtration. The solids were washed withEtOAc and the combined organic layers were washed with aqueous sodiumbicarbonate solution, brine, and were dried over sodium sulfate.Filtration and evaporation of all volatiles yielded the product.

ES/MS 355.0 (M+H⁺).

8-chloro-6-(((S)-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)(4-fluorophenyl)methyl)amino)-4-(((R)-3-fluoro-1-phenylpropyl)amino)quinoline-3-carbonitrile

(R)-6-amino-8-chloro-4-((3-fluoro-1-phenylpropyl)amino)quinoline-3-carbonitrile(50 mg, 0.14 mmol), CuI (1.4 mg, 0.05 eq) and2,6-bis((4S,5R)-4,5-diphenyl-4,5-dihydrooxazol-2-yl)pyridine [oxazolineligand] (4.4 mg, 0.06 eq) were sonicated in MeOH (2.0 mL) for ˜1 minute.Alkynyl acetate (68 mg, 0.35 mmol) and di-isopropyl ethyl amine (22 mg,0.17 mmol) were added and the reaction was stirred overnight.Cyclopropylazide (16 mg) was added and the reaction was stirred foradditional 16 hrs at room temperature. Solvents were removed in vacuoand the crude material was purified by RP-HPLC (eluent: water/MeCN*0.1%TFA) to yield the product as trifluoroacetate salt.

ES/MS 572.0 (M+H⁺).

Example 12 Procedure 12

(S)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)-6-((indolin-4-yl(1-isopropyl-1H-1,2,3-triazol-4-yl)methyl)amino)quinoline-3-carbonitrile

(S)-tert-butyl4-(((8-chloro-4-((3-chloro-4-fluorophenyl)amino)-3-cyanoquinolin-6-yl)amino)(1-isopropyl-1H-1,2,3-triazol-4-yl)methyl)indoline-1-carboxylate(45 mg, 0.065 mmol) was dissolved in DCM and trifluoroacetic acid andstirred at room temperature. After 30 minutes the reaction mixture wasconcentrated to dryness and the residue purified by RP-HPLC (eluent:water/MeCN*0.1% TFA) to yield the product as trifluoro acetate salt.

ES/MS 586.9 (M+H⁺).

Example 13 Procedure 13

(S)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(2-ethylisoindolin-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile

(S)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(isoindolin-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile(80.0 mg, 0.12 mmol) was dissolved in MeOH (3 mL) and AcOH (1 mL) atroom temperature. Acetaldehyde (0.066 mL, 1.17 mmol) and polymer boundPS—CNBH₃ (467 mg, 1.17 mmol) were then added and the reaction stirred atroom temperature. After 1 hour additional acetaldehyde (0.066 mL, 1.17mmol) and polymer bound PS—CNBH₃ (467 mg, 1.17 mmol) were added. After 1additional hour the PS—CNBH₃ was removed via vacuum filtration and thefiltrate concentrated to dryness. The resulting crude residue waspurified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the productas trifluoro acetate salt.

ES/MS 712.1 (M+H⁺).

Example 14 Procedure 14

(S)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(2-(oxetan-3-yl)isoindolin-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile

(S)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(isoindolin-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile(15 mg, 0.022 mmol) was dissolved in a 1:1 mixture of THF and DCE afterwhich oxetanone (0.007 mL, 0.11 mmol) and sodium triacetoxyborohydride(23.2 mg, 0.11 mmol) were added. After 1.5 hours the reaction mixturewas poured into saturated aqueous NaHCO₃ and extracted with EtOAc. Thecombined organic phases were washed with brine, dried over MgSO₄ andconcentrated. The crude residue was purified by RP-HPLC (eluent:water/MeCN*0.1% TFA) to yield the product as trifluoro acetate salt.

ES/MS 740.0 (M+H⁺).

Example 15 Procedure 15

(S)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(2-(2-hydroxyacetyl)isoindolin-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile

(S)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(isoindolin-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile(10.0 mg, 0.015 mmol) was dissolved in DMF (1 mL) after which glycolicacid (5.6 mg, 0.073 mmol), diisopropylethylamine (0.008 mL, 0.044 mmol)and HATU (7.1 mg, 0.022 mmL) were added at room temperature. Thereaction mixture was stirred for 20 minutes at which point it was pouredinto water (4 mL) and extracted with EtOAc (3×8 mL). The combinedorganic phases were washed with brine (5 mL), dried over MgSO₄ andconcentrated. The crude residue was purified by RP-HPLC (eluent:water/MeCN*0.1% TFA) to yield the product as trifluoro acetate salt.

ES/MS 742.1 (M+H⁺).

Example 16 Procedure 16

8-chloro-6-(((S)-(1-(1,1-difluoro-2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)(pyridin-3-yl)methyl)amino)-4-(((R)-1-phenylpropyl)amino)quinoline-3-carbonitrile

Ethyl 2-azido-2,2-difluoroacetate (47 mg, 0.29 mmol) was added to asolution of8-chloro-4-(((R)-1-phenylpropyl)amino)-6-(((R)-1-(pyridin-3-yl)prop-2-yn-1-yl)amino)quinoline-3-carbonitrile(130 mg, 0.26 mmol) and copper(I) thiophene-2-carboxylate (4.9 mg, 0.026mmol) in THF (2 mL). After 1 h the solvent was removed under reducedpressure. The residue was taken up in methanol (6 mL) and sodiumborohydride (19.5 mg, 0.52 mmol) was added to the solution. After 1 hthe reaction was quenched with water and extracted with ethyl acetate(3×10 mL). The combined organic phases were washed with brine, driedover sodium sulfate and concentrated. The residue was subjected to flashchromatography (0-100% (20% methanol in ethyl acetate) vs hexanes). Thefractions containing product were combined and the solvent was removedunder reduced pressure. The residue was taken up in methanol/water withtwo drops of trifluoroacetic acid and subjected to preparative HPLCeluted with acetonitrile/water with 0.1% trifluoroacetic acid. Fractionscontaining product were combined and subjected to lyophilization,providing8-chloro-6-(((S)-(1-(1,1-difluoro-2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)(pyridin-3-yl)methyl)amino)-4-(((R)-1-phenylpropyl)amino)quinoline-3-carbonitrile.

¹H NMR (400 MHz, DMSO-d6) δ 8.92-8.83 (m, 1H), 8.67 (d, J=9.5 Hz, 1H),8.65-8.58 (m, 1H), 8.24 (d, J=3.3 Hz, 1H), 8.15 (d, J=7.7 Hz, 1H),7.64-7.56 (m, 2H), 7.52 (d, J=8.3 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H),7.39-7.29 (m, 2H), 7.29-7.16 (m, 6H), 6.54 (d, J=7.8 Hz, 1H), 5.47 (q,J=7.6 Hz, 1H), 4.32 (t, J=12.0 Hz, 2H), 2.11 (m, 1H), 2.04-1.83 (m, 1H),0.93 (t, J=7.3 Hz, 3H).

ES/MS 575.1 (M+H⁺).

Example 17 Procedure 17(S)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(6-isopropoxypyridin-3-yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile

NaH (60% dispersion in mineral oil, 26.6 mg, 0.66 mmol) added to iPrOH(2 mL) at 0° C. for 20 minutes.(S)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(6-fluoropyridin-3-yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile(22 mg, 0.033 mmol) in DMF (0.5 mL) then added to newly formed alkoxide.The cold bath was removed and the resulting solution heated to 70° C.for 1 hour. The reaction mixture was quenched by water (1 mL) andextracted with EtOAc (3×8 mL). The combined organic phases were thenwashed with brine (5 mL), dried over MgSO₄ and concentrated. The cruderesidue was purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yieldthe product as trifluoro acetate salt.

Example 18 Procedure 18(S)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(tetrahydro-2H-pyran-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile

(S)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(3,6-dihydro-2H-pyran-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile(20.0 mg, 0.023 mmol), 10% Pd/C (2.5 mg, 0.002 mmol) and EtOH (1.5 mL)were combined and H₂ was bubbled through the reaction mixture for 5minutes. The reaction mixture was allowed to stir overnight under 1 atmof H₂ after which it was filtered through celite washing with EtOAc andEtOH. The filtrate was then concentrated and purified by RP-HPLC(eluent: water/MeCN*0.1% TFA) to yield the product as trifluoro acetatesalt.

Example 19 Procedure 19(S)-6-(((1-cyclopropyl-1H-1,2,3-triazol-4-yl)(3-oxoisoindolin-4-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrile

(S)-6-(((2-acetyl-3-oxoisoindolin-4-yl)(1-cyclopropyl-1H-1,2,3-triazol-4-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrile(34 mg, 0.059 mmol) was dissolved in MeOH (2 mL) at room temperature.NaOH (1.0M aq, 0.30 mL, 0.30 mmol) was added and the reaction stirredfor 30 minutes. HCl ((1.0M aq, 0.30 mL, 0.30 mmol) was added after whichthe reaction mixture was poured into water (3 mL) and extracted withEtOAc (3×8 mL). The combined organic phases were washed with brine (5mL), dried over MgSO₄ and concentrated. The crude residue was purifiedby RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the product astrifluoro acetate salt.

Example 20 Procedure 208-chloro-4-(3-chloro-4-fluoroanilino)-6-[[(S)-[1-(1-ethylpiperidin-4-yl)triazol-4-yl]-(1,3-thiazol-4-yl)methyl]amino]quinoline-3-carbonitrile

The title compound was prepared as conditions for the final step asfollows:(S)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)-6-(((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(thiazol-4-yl)methyl)amino)quinoline-3-carbonitrile(74.31 mg, 0.13 mmol) was dissolved in 1.20 mL of 3:12-methyltetrahyrdofuran: acetic acid and treated with acetaldehyde(10.52 μl, 0.19 mmol) and PS—BH₃CN (polystyrene supportedcyanoborohydride, 58 mg, 2.28 mmol/g). The mixture was stirredovernight. Additional acetaldehyde and 0.1 mL of methanol were added,and the reaction was complete in one hour. The resin was filtered andthe resulting filtrate was concentrated, dissolved in dichloromethane,washed with saturated sodium bicarbonate, dried over sodium sulfate,filtered and concentrated. Purification using RP-HPLC (eluent:water/MeCN*0.1% TFA) provided the product as trifluoroacetate salt.

¹H NMR (400 MHz, CD₃OD) δ 9.02 (m, 1H), 8.46 (s, 1H), 8.01 (m, 1H), 7.68(m, 1H), 7.60 (m, 1H), 7.52 (m, 1H), 7.33 (m, 4H), 6.31 (s, 1H), 3.75(m, 2H), 3.25-3.13 (m, 3H), 2.45 (m, 2H), 2.36 (m, 2H), 2.25-2.01 (m,2H), 1.37 (m, 3H),

ES/MS 622.0 (M+H⁺)

Example 21 Procedure 218-chloro-4-(3-chloro-4-fluoroanilino)-6-[[(S)-(1-propan-2-yltriazol-4-yl)-[5-(pyrrolidine-1-carbonyl)pyridin-3-yl]methyl]amino]quinoline-3-carbonitrile

A misture of(S)-6-(((5-bromopyridin-3-yl)(1-isopropyl-1H-1,2,3-triazol-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile(200 mg, 0.32 mmol), pyrrolidine (580.6 mg, 8.16 mmol), and Dichloro1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane (269.1mg, 0.32 mmol) in DMF (1.2 ml) was degassed and purged with carbonmonoxide twice, the heated at 80° C. for 5 hours. The solution wascooled and poured into water, then extracted with ethyl acetate. Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated. The crude product was purified by RP-HPLC (eluent:water/MeCN*0.1% TFA) to yield the product as trifluoroacetate salt.

ES/MS 644.1 (M+H⁺)

Example 22 Procedure 22

6-(((S)-(6-fluoropyridin-3-yl)(1-methyl-1H-1,2,3-triazol-4-yl)methyl-d)amino)-4-(((R)-1-phenylpropyl)amino)quinoline-3,8-dicarbonitrile

1.0 M solution of TBAF (0.38 mL, 0.38 mmol) in THF was added to thestirring solution of6-(((R)-(6-fluoropyridin-3-yl)(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)deteromethyl)amino)-4-(((R)-1-phenylpropyl)amino)quinoline-3,8-dicarbonitrile(150 mg, 0.25 mmol) in THF (5 mL). The resulting solution was stirredfor 2 h then concentrated to give crude material. HPLC purificationafforded the title compound.

1H NMR (400 MHz, DMSO-d6) δ 8.49-8.38 (m, 1H), 8.28 (d, J=5.1 Hz, 1H),8.13-8.02 (m, 2H), 7.84 (t, J=2.4 Hz, 1H), 7.65-7.52 (m, 2H), 7.42-7.31(m, 1H), 7.31-7.15 (m, 4H), 5.49 (q, J=7.7 Hz, 1H), 4.04 (s, 3H),3.20-3.11 (m, 1H), 2.20-2.05 (m, 1H), 2.05-1.85 (m, 1H), 1.63-1.50 (m,1H), 1.37-1.20 (m, 1H), 0.99-0.83 (m, 3H).

ES/MS 519.2 (M+H⁺).

Example 23 Procedure 23

The CuI (2.6 mg, 0.014 mmol) and ligand (8.7 mg, 0.017 mmol) weresuspended in MeOH (1 mL) and sonicated under argon for 5 min. Theremaining MeOH was added followed by the acetate (70.3 mg, 0.36 mmol)and amine (80 mg, 0.27 mmol) and DIPEA (43 mg, 0.33 mmol) in that orderat room temperature. After 14 h the N-alkylation reactions was complete.Evaporation and purification on silica get (eluent: EtOAc in hexanes)yielded 95 mg of N-alkylated product. The material was taken into THF (2mL). Azide stock (1 mL/1 eq.), Cu and CuSO4 were added. Stirring at roomtemperature for 1 hr. Diluted with EtOAc, washed with NaHCO3 brine anddried over sodium sulfate. Filtration, evaporation, and purification viaRP-HPLC (eluent: water/MeCN*0.1 TFA) yielded the product as the TFAsalt.

¹H NMR (400 MHz, Methanol-d4) δ 8.79 (s, 1H), 8.49 (s, 1H), 8.00 (s,1H), 7.69 (d, J=2.3 Hz, 1H), 7.26 (d, J=2.3 Hz, 1H), 6.31 (s, 1H), 5.91(t, J=54.8 Hz, 1H), 4.09 (d, J=13.9 Hz, 1H), 3.93 (d, J=14.0 Hz, 1H),2.56 (s, 3H), 1.50 (m, 4H), 1.05 (s, 9H).

Example 24 Procedure 24

The SM (38 mg, 0.05 mmol), Zn (0.4 mg, 0.007 mmol), PddppfCl₂ (0.8 mg,0.001 mmol) and Zn(CN)₂ (7.1 mg, 0.061 mmol) were combined indimethylacetamide (1 mL) and degassed for 2 min. The mixture was heatedin a microwave reactor at 200° C. for 20 min. The mixture was filteredand purified via RP-HPLC. The product fractions were combined andsubjected to lyophilization, providing the desired compound as TFA salt.

¹H NMR (400 MHz, Methanol-d4) δ 8.78 (s, 1H), 8.37 (s, 1H), 8.02 (s,1H), 7.83 (d, J=2.5 Hz, 1H), 7.44 (d, J=2.5 Hz, 1H), 6.32 (s, 1H), 5.92(t, J=54.8 Hz, 1H), 3.96 (d, J=13.9 Hz, 1H), 3.80 (d, J=13.9 Hz, 1H),2.56 (s, 3H), 1.50 (m, 4H), 1.02 (s, 9H).

Example 25 Procedure 25

SM (0.04 g, 0.06 mmol), Zn powder (0.006 g, 0.09 mmol), Pd(dppf)Cl2(0.009 g, 0.012 mmol) and Zn(CN)₂ (0.021 g, 0.18 mmol) were combined indimethylacetamide (0.7 mL) and degassed for 1 min. The mixture washeated in a microwave reactor at 200° C. for 15 min. The mixture wasfiltered and purified via RP-HPLC. The product fractions were combinedand subjected to lyophilization, providing the desired compound as TFAsalt.

¹H NMR (400 MHz, Methanol-d4) δ 9.61 (s, 1H), 8.69 (d, J=6.1 Hz, 1H),8.33 (s, 1H), 8.23 (s, 1H), 8.17 (d, J=7.6 Hz, 1H), 8.16 (d, J=6.1 Hz,1H), 8.02 (d, J=7.6 Hz, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.02 (d, J=2.5 Hz,1H), 6.91 (s, 1H), 3.82 (d, J=13.8 Hz, 1H), 3.42 (d, J=13.7 Hz, 1H),1.79-1.55 (m, 4H), 0.62 (s, 9H).

Example 26 Procedure 26

To(S)-8-chloro-6-(((1-cyclopropyl-1H-1,2,3-triazol-4-yl)(2-fluoropyridin-3-yl)methyl-d)amino)-4-(neopentylamino)quinoline-3-carbonitrile(TFA salt, 24 mg, 0.04 mmol) was added dimethylamine (2M solution inMeOH, 0.9 mL). The solution was heated to 100° C. (external temperature,μW) for 8 h. The resulting solution was concentrated, purified viapreparative HPLC (Gemini column, 10-42% MeCN/H₂O/0.1% TFA) andlyophilized to provide the product as the corresponding TFA salt.

¹H NMR (400 MHz, Methanol-d4) δ 8.38 (s, 1H), 8.06 (dd, J=5.4, 1.8 Hz,1H), 7.92 (s, 1H), 7.81 (dd, J=7.6, 1.8 Hz, 1H), 7.49 (d, J=2.3 Hz, 1H),7.06 (d, J=2.3 Hz, 1H), 7.02 (dd, J=7.6, 5.4 Hz, 1H), 4.10 (d, J=14.0Hz, 1H), 3.78 (ddd, J=11.4, 7.1, 4.2 Hz, 1H), 3.63 (d, J=14.0 Hz, 1H),2.97 (s, 6H), 1.12-1.02 (m, 4H), 0.91 (s, 9H).

Example 27 Procedure 27

Cu(I)iodide (16.5 mg, 0.09 mmol) and bis-oxazoline ligand (54.2 mg) weresonicated in MeOH (10 mL) for 5 minutes. The mixture was cooled to 0° C.A solution of alkynyl actetate (687 mg, 3.3 mmol) in MeOH (7 mL) wasadded followed by quinoline (500 mg, 1.73 mmol) and di-iso-propyl ethylamine (268.5 mg, 2.08 mmol). Stirring at 0° C. was continued. Afterconsumption of starting material, the reaction volume was reduced andthe crude material was purified via silica gel chromatography (e1: EtOAcin hexanes) to yield the product.

¹H NMR (400 MHz, Acetonitrile-d3) δ 8.34 (s, 1H), 8.14 (t, J=8.2 Hz,1H), 7.43 (d, J=2.3 Hz, 1H), 6.95-6.82 (m, 2H), 5.98 (t, J=6.4 Hz, 1H),5.64 (dd, J=7.1, 2.2 Hz, 1H), 5.52 (d, J=7.2 Hz, 1H), 3.81 (dd, J=13.4,6.7 Hz, 1H), 3.67 (dd, J=13.4, 6.0 Hz, 1H), 2.88 (d, J=2.2 Hz, 1H), 2.56(s, 3H), 2.23 (s, 1H), 1.01 (s, 9H).

ES/MS m/z: 436.2.

The alkyne starting material (1.6 g, 3.67 mmol) was dissolved in MeTHF(16 mL) and azide solution in MTBE (0.5 M, 7.34 mL) andcopper(I)thiophenecarboxylate (24 mg, 0.18 mmol) were added and stirringat room temperature was continued. After the SM was consumed, thereaction was diluted with EtOAc and was washed with aqueous sodiumbicarbonate solution and dried over sodium sulfate. Filtration andevaporation of solvents gives crude material which was purified viasilica gel chromatography (e1. EtOAc in hexanes) to yield product.

¹H NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 7.93 (t, J=8.1 Hz, 1H),7.41 (s, 1H), 7.35 (d, J=2.3 Hz, 1H), 6.80 (dd, J=8.4, 3.2 Hz, 1H), 6.25(s, 1H), 5.93 (s, 1H), 5.91 (t, J=56.0 Hz, 1H), 5.27 (s, 1H), 3.57 (m,2H), 2.58 (s, 3H), 1.55-1.50 (m, 4H), 0.94 (s, 9H).

ES/MS m/z: 569.6.

Example 28 Procedure 28(S)-8-chloro-6-(((1-cyclopropyl-5-iodo-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

Copper (I) iodide (172.5 mg, 0.906 mmol) and iodine monochloride (147mg, 0.906 mmol) were added to a solution of(R)-8-chloro-6-((1-(6-fluoro-2-methylpyridin-3-yl)prop-2-yn-1-yl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(394 mg, 0.906 mmol), cyclopropyl azide (79.1 mg 0.906 mmol), andtriethylamine (151.6 uL, 1.09 mmol) in tetrahydrofuran (15 mL). After 16h the reaction was diluted with ethyl acetate (50 mL) and washed withwater (25 mL) and brine (25 mL). The organic phase was dried over sodiumsulfate and the solvent was removed under reduced pressure. The materialwas mixed with ethyl acetate (5 mL) and the solid was isolated byfiltration providing(S)-8-chloro-6-(((1-cyclopropyl-5-iodo-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile.

Example 29 Procedure 29(S)-8-Chloro-6-(((1,5-dicyclopropyl-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

1,4-Dioxane (4.0 mL) and water (0.5 mL) were added to(S)-8-Chloro-6-(((1-cyclopropyl-5-iodo-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(100 mg, 0.155 mmol), cyclopropylboronic acid (20 mg, 0.223 mmol),tetrakis(triphenylphosphine)palladium(O) (35.8 mg, 0.031 mmol), andpotassium carbonate (42.8 mg, 0.310 mmol) in a microwave vial. Thereaction was heated in a microwave reactor for 20 minutes at 130° C. Themixture was diluted with ethyl acetate (10 mL) and washed with brine (5mL). The organic phase was dried over sodium sulfate and the solvent wasremoved under reduced pressure. The residue was subjected to flashchromatography (0-100% ethyl acetate/hexanes). The fractions containingproduct were combined and the solvent was removed under reducedpressure. The residue was taken up in methanol (1 mL) and water (0.5 mL)with 2 drops of trifluoroacetic acid and subjected to preparative HPLC.The clean fractions were combined and subjected to lyophilization,providing(S)-8-Chloro-6-(((1,5-dicyclopropyl-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile.

Example 30 Procedure 30(S)-8-chloro-6-(((1-cyclopropyl-5-fluoro-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

Acetonitrile (1.0 mL) and water (1.0 mL) were added to(S)-8-Chloro-6-(((1-cyclopropyl-5-iodo-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(50 mg, 0.078 mmol) and potassium fluoride (22.5 mg, 0.388 mmol) in amicrowave vial. The vial was sealed and the reaction was heated in amicrowave reactor at 180° C. for 12 minutes. The reaction was dilutedwith ethyl acetate (10 mL) and washed with brine (5 mL). The organicphase was dried over sodium sulfate and the solvent was removed underreduced pressure. The residue was subjected to flash chromatography(0-100% ethyl acetate/hexanes). The fractions containing product werecombined and the solvent was removed under reduced pressure. The residuewas taken up in methanol (1 mL) and water (0.5 mL) with 2 drops oftrifluoroacetic acid and subjected to preparative HPLC. The cleanfractions were combined and subjected to lyophilization, providing(S)-8-chloro-6-(((1-cyclopropyl-5-fluoro-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile.

Example 31 Procedure 31(S)-8-chloro-6-(((1-cyclopropyl-5-methoxy-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

solution of(S)-8-chloro-6-(((1-cyclopropyl-5-fluoro-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(42.6 mg, 0.079 mmol) in tetrahydrofuran (2.0 mL). The solution washeated at 90° C. for 30 minutes and the reaction was quenched with 2drops of acetic acid. The solution was diluted with ethyl acetate (15mL) and washed with saturated sodium bicarbonate (5 mL) and brine (5mL). The organic phase was dried over sodium sulfate and the solvent wasremoved under reduced pressure. The residue was subjected to flashchromatography (0-100% ethyl acetate/hexanes). The fractions containingproduct were combined and the solvent was removed under reducedpressure. The residue was taken up in methanol (1 mL) and water (0.5 mL)with 2 drops of trifluoroacetic acid and subjected to preparative HPLC.The clean fractions containing product were combined and subjected tolyophilization, providing(S)-8-chloro-6-(((1-cyclopropyl-5-methoxy-H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile.

Example 32 Procedure 32

Aldehyde (223 mg, 1.4 mmol) was dissolved in acetonitrile (8 mL).Triethylamine (0.29 mL, 2.1 mmol) and DMAP (34 mg, 0.28 mmol) were addedfollowed by Boc₂O (365 mg, 1.7 mmol) and the resulting mixture stirredfor 2 minutes. Upon completion the reaction contents were concentrateddirectly then purified via silica gel chromatography (EtOAc in hexanes)to yield the product.

The newly formed material was taken up in THF (15 mL) and brought to 0°C. Ethynylmagnesium bromide (0.5M in THF, 3.7 mL, 1.8 mmol) was addeddropwise and the resulting solution stirred for 30 minutes at whichpoint acetic anhydride (0.29 mL, 3.1 mmol) was added and the reactioncontents allowed to warm to room temperature over 1 h. The reaction wasquenched by the addition of saturated aqueous NH₄Cl and extracted withEtOAc. The organic layers were washed with brine, dried over magnesiumsulfate, filtered and concentrated to give the crude propargyl acetatewhich was used without further purification.

The CuI (6.6 mg, 0.035 mmol) and ligand (22 mg, 0.042 mmol) weresuspended in MeOH (5 mL) and sonicated under argon for 5 min. Theacetate (136 mg, 0.42 mmol) as a solution in MeOH (2 mL), amine (100 mg,0.35 mmol) and DIPEA (54 mg, 0.42 mmol) were added in that order at roomtemperature. After 2 h reaction mixture was concentrated directly andpurified on silica gel (EtOAc in hexanes) to give the alkylated product.

The material was taken into THF (2 mL). Azide stock (1 mL/1 eq.), Cu andCuSO4 were added and the resulting mixture stirred at room temperaturefor 30 min. Diluted with EtOAc, washed with water, brine and dried overmagnesium sulfate. Filtration and concentration gave the crude productwhich was then stirred in 1 mL of a 1:1 DCM:trifluoroacetic acid mixturefor 30 min. The DCM and TFA were removed by rotary evaporation afterwhich the crude residue was purified RP-HPLC (eluent: water/MeCN*0.1TFA) yielded the product as TFA salt.

Example 33 Procedure 33

A solution of the alkyne starting material (50 mg, 0.115 mmol) indeuterated methanol (CD₃OD, 2 mL) was treated with azide solution in DCM(25% by weight, 80 mg, 0.138 mmol) and copper(I)thiophenecarboxylate (1mg) at room temperature. After 1 hour, the reaction was diluted withEtOAc and was washed with aqueous sodium bicarbonate solution and driedover sodium sulfate. Filtration and evaporation of solvents gives crudematerial which was purified via reverse phase HPLC to yield cleanproduct.

¹H NMR (400 MHz, Acetonitrile-d3) δ 8.44 (s, 1H), 7.82 (t, J=8.2 Hz,1H), 7.49 (d, J=2.3 Hz, 1H), 6.84 (dd, J=8.4, 3.2 Hz, 1H), 6.78 (s, 1H),6.17 (s, 1H), 3.83 (m, 2H), 1.78-1.65 (m, 2H), 1.65 (m, 2H), 0.95 (s,9H).

ES/MS m/z: 588.31.

Example 34 Procedure 34

A mixture of(S)-8-iodo-4-(neopentylamino)-6-((quinolin-5-yl(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)amino)quinoline-3-carbonitrile(61 mg, 0.09 mmol) and Cuprous cyanide (23.53 mg, 0.26 mmol) in DMF (2mL) was heated at 135° C. in the microwave for 15 minutes. The solutionwas treated with Si-thiol, filtered and purified by reverse phase HPLCto provide(S)-4-(neopentylamino)-6-((quinolin-5-yl(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)amino)quinoline-3,8-dicarbonitrileas the bis-trifluoroacetate salt.

¹H NMR (400 MHz, Methanol-d4) δ 9.11 (s, 1H), 9.04 (d, J=8.7 Hz, 1H),8.30 (s, 1H), 8.21 (s, 1H), 8.18-8.10 (m, 1H), 7.99-7.90 (m, 1H),7.90-7.82 (m, 2H), 7.80 (s, 1H), 7.14-7.08 (m, 1H), 6.94 (s, 1H), 3.79(d, J=13.8 Hz, 1H), 3.48 (d, J=13.8 Hz, 1H), 1.75-1.56 (m, 4H), 0.66 (s,9H).

ES/MS m/z: 596.35.

Example 35 Procedure 35

N-Ethyldiisopropylamine (15.47 μl, 0.09 mmol) was added to a mixture of(S)-1-(4-(((8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)amino)(6-fluoro-2-methylpyridin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)cyclopropane-1-carboxylicacid (25 mg, 0.044 mmol),2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), 99% (17.27 mg, 0.05 mmol), and 2MDimethylamine solution (44.4 μl, 0.053 mmol) in dimethylformamide (1mL). After 3 hours half of the solvent was removed under reducedpressure. The solution was diluted with methanol (0.75 mL) water (0.5mL) and TFA (50 uL). This solution was subjected to preperative HPLC.The cleaner fractions containing product were combined and subjected tolyophilization, providing the desired compound. The lyophilized solidwas taken up in methanol (0.5 mL) and passed through a carbonate resinwith methanol washing (5 mL). The solvent was removed under reducedpressure and the residue was taken up in ACN (1 mL) and water (1 mL)with TFA (0.02 mL) and subjected to lyophilization providing the(S)-1-(4-(((8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)amino)(6-fluoro-2-methylpyridin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)-N,N-dimethylcyclopropane-1-carboxamide.

Example 36 Procedure 36

A solution of(S)-8-chloro-6-(((1-cyclopropyl-5-iodo-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(33 mg, 0.051 mmol), copper (I) cyanide (13.7 mg, 0.15 mmol) indimethylformamide (1 mL) was heated in a microwave reactor at 200 C for20 min. The mixture was diluted with ethyl acetate (10 ml) and washedwith 5% lithium chloride (2×5 mL) and brine (5 mL). The organic phasewas dried over sodium sulfate and the solvent was removed under reducedpressure. The residue was subjected to flash chromatography (0-100%EtOAc/hexanes). The fractions containing product were combined and thesolvent was removed under reduced pressure. The residue was taken up inwater (0.5 ml) and methanol (1 mL) with 2 drops of TFA and subjected topreperative HPLC. The clean fractions combined and subjected tolyophilization, providing(S)-8-chloro-6-(((5-cyano-1-cyclopropyl-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile.

Example 37 Procedure 37

A solution of tert-Butyl(S)-3-(((3-cyano-8-iodo-4-(neopentylamino)quinolin-6-yl)amino)(1-cyclopropyl-1H-1,2,3-triazol-4-yl)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate(60.3 mg, 0.082 mmol), tetrakis(triphenylphosphine)palladium(O) (7.55mg, 0.01 mmol), and zinc cyanide (23.96 mg, 0.20 mmol) was degassed withargon for 10 minutes, The mixture was heated in a sealed vial at 100° C.After 36 h the reaction was diluted with ethyl acetate (20 ml) andwashed with 5% lithium chloride (2×5 mL) and brine (5 mL). The organicphase was dried over sodium sulfate and the solvent was removed underreduced pressure. The residue was subjected to flash chromatography(0-100% (20% methanol/ethyl acetate)/hexanes). The fractions containingproduct were combined and the solvent was removed under reducedpressure, providing tert-butyl(S)-3-((1-cyclopropyl-1H-1,2,3-triazol-4-yl)((3,8-dicyano-4-(neopentylamino)quinolin-6-yl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate.

Zinc bromide (88.6 mg, 0.39 mmol) was added to a solution of tert-butyl(S)-3-((1-cyclopropyl-H-1,2,3-triazol-4-yl)((3,8-dicyano-4-(neopentylamino)quinolin-6-yl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate(50.2 mg, 0.079 mmol) in nitromethane (5 mL). After 50 minutes thesolvent was removed under reduced pressure. The residue was partitionedbetween ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL).Solid formed which was removed by filtration. The organic phase waswashed with saturated sodium bicarbonate (10 mL) and brine (10 mL). Theorganic phase was dried over sodium sulfate and the solvent was removedunder reduced pressure, providing(S)-6-(((1-cyclopropyl-1H-1,2,3-triazol-4-yl)(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrile.

3-Oxetanone (38.75 μl, 0.6 mmol) was added to a mixture of(S)-6-(((1-cyclopropyl-1H-1,2,3-triazol-4-yl)(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrile(32.5 mg, 0.060 mmol) and sodium triacetoxyborohydride (128.1 mg, 0.60mmol) in tetrahydrofuran (2 mL) dichloroethane (2 mL) and heated at 40°C. for 16 h. The mixture was diluted with ethyl acetate (10 mL) andwashed with saturated sodium bicarbonate (2×5 mL) and brine (5 mL). Theorganic phase was dried over sodium sulfate and he solvent was removedunder reduced pressure. The residue was subjected to flashchromatography (0-100% (20% methanol in ethyl acetate)/hexanes). Thefractions containing product were combined and the solvent was removedunder reduced pressure. The residue was taken up in methanol (0.5mL)/water (0.5 mL) with 2 drops of TFA and subjected to preperative HPLC(eluted with 0-100% acetonitrile an water with 0.05% trifluoroaceticacid). The clean fractions were combined and subjected tolyophilization,(S)-6-(((1-cyclopropyl-1H-1,2,3-triazol-4-yl)(6-(oxetan-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrile.

Example 38 Procedure 38

(S)-6-((benzo[d]thiazol-7-yl(1-cyclopropyl-1H-1,2,3-triazol-4-yl)methyl)amino)-4-(tert-butoxyamino)quinoline-3,8-dicarbonitrile

To(S)-6-((benzo[d]thiazol-7-yl(1-cyclopropyl-1H-1,2,3-triazol-4-yl)methyl)amino)-4-(tert-butoxyamino)-8-iodoquinoline-3-carbonitrile(59 mg, 0.093 mmol) in N-methyl-2-pyrrolidone (1 mL) was added zinccyanide (27 mg, 0.232 mmol) and palladium tetrakis triphenylphosphine (9mg, 0.007 mmol). The reaction mixture was degassed with nitrogen for 5minutes, then stirred at 100° C. overnight. The reaction was thenbrought to room temperature and diluted with water and EtOAc. Aqueouslayer was extracted once more with EtOAc. Combined organics were washedwith water, brine, dried (Na₂SO₄) and concentrated to give the crudeproduct which was purified by HPLC (eluent: water/MeCN*0.1% TFA) toyield the title product. ES/MS 536.20 (M+H⁺).

Example 39 Procedure 39

(S)-6-((benzo[d]thiazol-7-yl(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-8-(methylsulfonyl)-4-(neopentylamino)quinoline-3-carbonitrile

To(S)-6-((benzo[d]thiazol-7-yl(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-8-bromo-4-(neopentylamino)quinoline-3-carbonitrile(31 mg, 0.047 mmol), (L)-proline (1.1 mg, 0.009 mmol), Cu(I)I (1 mg,0.005 mmol), sodium methylsulfonate (5.8 mg, 0.057 mmol), and Cs₂CO₃ (15mg, 0.047 mmol) was added DMSO (0.8 mL). The reaction mixture was placedunder an atmosphere of nitrogen stirred at 110° C. overnight. Thereaction was then brought to room temperature and diluted with water andEtOAc. Aqueous layer was extracted once more with EtOAc. Combinedorganics were washed with water, brine, dried (Na₂SO₄) and concentratedto give the crude product which was purified by HPLC (eluent:water/MeCN*0.1% TFA) to yield the title product. ES/MS 655.7 (M+H⁺).

Example 40 Procedure 40

6-(((6-Fluoro-2-methylpyridin-3-yl)(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-4-(neopentylamino)quinoline-3-carbonitrile

6-(((6-Fluoro-2-methylpyridin-3-yl)(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-8-iodo-4-(neopentylamino)quinoline-3-carbonitrile(30 mg, 0.044 mmol), copper iodide (0.84 mg, 0.004 mg), and2-methyl-3-butyn-2-ol (18.6 mg, 0.22 mmol) were dissolved in Me-THF.Then Bis(triphenylphosphine)palladium(II) dichloride (3.1 mg, 0.004mmol) was add to the mixture followed by diethylamine (0.05 ml, 0.44mmol). The reaction was heated to 80 C for one hour, then diluted withEtOAc and brine, the organic layer was kept, dried over sodium sulfate,and concentrated. The crude residue was purified by RP-HPLC (eluent:water/MeCN*0.1% TFA) to yield the product as trifluoro acetate salt.

Example 41 Procedure 41

(S)-8-Chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-5-fluoro-4-(neopentylamino)quinoline-3-carbonitrile

(S)-8-Chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(100 mg, 0.18 mmol) was dissolved in ACN. Selectfluor (31.8 mg, 0.176mmol) was added to the stirring mixture. The reaction was stopped after20 minutes, diluted with EtOAc and water. The organic layer was driedover sodium sulfate, and concentrated. The product was purified bychromatography on silica gel (eluent: EtOAc/hexanes) to yield theproduct after lyophilization from water/MeCN.

Example 42 Procedure 42

(S)-5-bromo-8-chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-5-fluoro-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

N-Bromosuccinimide (7.8 mg, 0.044 mmol) was added to a solution of(S)-8-chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-5-fluoro-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(26 mg, 0.044 mmol) in acetonitrile (1 mL) at 0° C. After 24 h at roomtemperature trifluoroacetic acid (4 drops) was added and the mixture wasdiluted with water. The yellow solution was subjected to preparativeHPLC. The fractions containing product were combined and the solvent wasreduced pressure, providing the(S)-5-bromo-8-chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-5-fluoro-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrileas the TFA salt.

Example 43 Procedure 43

1-Azidobicyclo[1.1.1]pentane

A solution of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (429mg, 1.5 mmol) in acetonitrile (2 mL) was added to solution of thebicyclo[1.1.1]pentan-1-amine hydrochloride (150 mg, 1.25 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (420 mg, 4.2 mmol) in acetonitrile (3mL) dropwise over 1 min. After 16 h at RT the reaction was heated at 40C for 3 h. The reaction was assumed to be complete and was added to theClick reaction as is.

(S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile

2-Methyltetrahydrofuran (12 mL), copper powder (394 mg, 6.2 mmol) and(R)-8-chloro-6-((1-(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)prop-2-yn-1-yl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(500 mg, 1.03 mmol) were combined. Saturated copper (II) sulfate (0.6mL) was added followed by acetic acid (236 uL, 4.13 mmol). A solution of1-azidobicyclo[1.1.1]pentane (137 mg, 1.25 mmol) in acetonitrile (5mL—reaction mixture from above) was added. After 1 h the solids wereremoved by filtration. The mixture was partitioned with ethyl acetate(50 mL) and saturated ammonium chloride (50 mL). An emulsion formed witha light solid. The solid was removed by filtration through celite. Theorganic phase was washed with saturated ammonium chloride (50 mL),saturated sodium bicarbonate (4×50 mL) and brine (50 mL). The organicphase was dried over sodium sulfate and the solvent was removed underreduced pressure. The residue was subjected to flash chromatography(0-70% ethyl acetate/hexanes). The fractions containing product werecombined and the solvent was removed under reduced pressure. The residuewas taken up in acetonitrile (15 mL) and water (15 mL) and subjected tolyophilization, providing(S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile.

Example 44 Procedure 44

(S)-8-chloro-6-(((6-fluoro-2-methylpyridin-3-yl)(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

a mixture of the bromoalkane (54 mg, 0.09 mmol) in 4.4 ml toluene waspurged with argon for 45 minutes. It was heated to reflux and thenTris(trimethylsilyl)silane (43.74 mg, 0.18 mmol) was added, followed bydropwise addition of 2,2′-Azobisisobutyronitrile, 98% (1.44 mg, 0.01mmol) in 0.44 mL toluene. After 16 hours heating at reflux, anotherportion of the silane was added and heating was continued for 4 hoursmore. The mixture was concentrated and purified by RP-HPLC to yield theproduct as the trifluoroacetate salt.

Example 45 Procedure 45

(S)-8-chloro-6-(((6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3]oxazin-3-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrileand(S)-8-chloro-6-(((6-fluoro-2-methylpyridin-3-yl)(1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

(S)-8-chloro-6-(((5-fluoro-1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(37 mg, 0.07 mmol, prepared as for example 23) was dissolved in DMF andcooled in an ice water bath. Sodium hydride 60% dispersion in mineraloil (5.6 mg, 0.23 mmol) was added NaH and the mixture was allowed towarm to room temperature. After 1 hour, the reaction was complete byUPLC-MS and contained dehalogenated, uncyclized product as well.Purification by RP HPLC 15 minutes 10-49% gave the two productsindependently as the corresponding trifluoroacetate salts.

(S)-8-chloro-6-(((6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3]oxazin-3-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

ES/MS m/z: 535.34. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.42 (s, 1H),7.92 (m, 1H), 7.48 (s, 1H), 6.79 (m, 1H), 6.70 (s, 1H), 5.97 (s, 1H),4.35 (m, 4H), 3.90 (m, 1H), 3.68 (m, 1H), 2.50 (s, 3H), 2.23 (m, 2H),0.94 (s, 9H).

(S)-8-chloro-6-(((6-fluoro-2-methylpyridin-3-yl)(1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

ES/MS m/z: 537.27. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.41 (s, 1H),7.84 (m, 1H), 7.66 (m, 1H), 7.48 (m, 1H), 6.82 (m, 1H), 6.74 (m, 1H),6.15 (m, 1H), 4.42 (m, 2H), 3.76 (m, 2H), 3.48 (m, 2H), 2.51 (s, 3H),1.98 (m, 2H), 0.94 (s, 9H).

Example 46 Procedure 46

(S)-6-(((6-fluoro-2-methylpyridin-3-yl)(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-4-(neopentylamino)-8-(pyrimidin-5-yl)quinoline-3-carbonitrile

6-(((6-fluoro-2-methylpyridin-3-yl)(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-8-iodo-4-(neopentylamino)quinoline-3-carbonitrile(20 mg, 0.03 mmol), potassium carbonate (0.03 mL, 0.06 mmol), andpyrimidin-5-ylboronic acid (5.3 mg, 0.045 mmol) were dissolved in DME.Then bis(triphenylphosphine)palladium(II) dichloride (1.0 mg, 0.002mmol) was add to the mixture. The reaction was heated to 110° C. inmicrowave reactor for 5 minutes, then diluted with EtOAc and brine, theorganic layer was kept, dried over sodium sulfate, and concentrated. Thecrude residue was purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) toyield the product as trifluoro acetate salt.

Example 47 Procedure 47

(S)-8-chloro-6-(((6-fluoro-2-methylpyridin-3-yl)(5-iodo-1-(1-methylcyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

To(R)-8-chloro-6-((1-(6-fluoro-2-methylpyridin-3-yl)prop-2-yn-1-yl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(100 mg, 0.23 mmol) in MeTHF (2 mL) was added Copper(i) iodide (4 mg,0.02 mmol) and N-iodomorpholine hydriodide (95 mg, 0.28 mmol). Thesolution was stirred at room temperature for 5 h. The resulting solutionwas filtered through a carbonate resin and concentrated to give thecrude(S)-8-chloro-6-((1-(6-fluoro-2-methylpyridin-3-yl)-3-iodoprop-2-yn-1-yl)amino)-4-(neopentylamino)quinoline-3-carbonitrile.

To a solution of(S)-8-chloro-6-((1-(6-fluoro-2-methylpyridin-3-yl)-3-iodoprop-2-yn-1-yl)amino)-4-(neopentylamino)quinoline-3-carbonitrilein MeTHF (2 mL) was added triethylamine (0.05 mL, 0.36 mmol), Copper (I)iodide (4 mg, 0.02 mmol), and 1-azido-1-methylcyclopropane (0.5 mL, 0.5M in MTBE, 0.25 mmol). The resulting solution was stirred at roomtemperature for 3 days and then washed with aqueous bicarbonate. Theaqueous layer was back-extracted with EtOAc (2×), and the combinedorganic layers were dried over Na2SO4 and concentrated. The cruderesidue was purified by reverse-phase HPLC (10-60% MeCN/H₂O with 0.1%TFA) to provide the product as a TFA salt. The product was dissolved inEtOAc and washed with aqueous bicarbonate. The aqueous layer wasback-extracted with EtOAc (2×), and the combined organic layers weredried over Na₂SO4 and concentrated. The crude residue was purified bynormal-phase chromatography (10-50% EtOAc/CH₂Cl₂) to provide theproduct.

1H NMR (400 MHz, Methanol-d4) δ 8.51 (d, J=1.1 Hz, 1H), 7.81 (t, J=8.1Hz, 1H), 7.65 (d, J=2.3 Hz, 1H), 6.86 (dd, J=8.6, 2.7 Hz, 1H), 6.83 (d,J=2.3 Hz, 1H), 6.07 (s, 1H), 4.13 (d, J=13.9 Hz, 1H), 3.70 (d, J=13.9Hz, 1H), 2.40 (s, 3H), 1.64 (s, 3H), 1.44-1.31 (m, 2H), 1.22 (t, J=2.0Hz, 2H), 0.89 (s, 9H).

ES/MS: 659.255 (M+H⁺).

Example 48 Procedure 48

(S)-8-chloro-6-(((6-fluoro-2-methylpyridin-3-yl)(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)(methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

To a slurry of6-amino-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile (1 g, 3.46mmol) in H₂O (35 mL) and H2SO4 (1.8 mL) at 0° C. (external) was dropwiseadded 1.5M aqueous NaNO₂ (2.8 ml). The resulting solution was stirred at0° C. for 1.5 h before potassium iodide (1.2 g, 7.23 mmol) in H₂O (15mL) was added. The resulting slurry was vigorously stirred at roomtemperature for 18 h. The slurry was neutralized with NaOH (2M),filtered, and washed twice with H2O. The resulting filtrate wasdissolved in EtOAc and washed with aqueous NaCl. The aqueous layer wasback-extracted with EtOAc and the combined organic layers were driedover MgSO4 and concentrated. The crude material was purified by SiO₂chromatography (5-25-100% EtOAc/Hex, 20% MeOH/EtOAc wash) to provide thedesired product.

1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=1.7 Hz, 1H), 8.55 (s, 1H), 8.25(d, J=1.5 Hz, 1H), 8.19 (t, J=7.0 Hz, 1H), 3.72 (d, J=6.8 Hz, 2H), 0.96(s, 9H).

ES/MS: 400.428 (M+H⁺).

To a solution of(S,E)-2-methyl-N-(3-(trimethylsilyl)prop-2-yn-1-ylidene)propane-2-sulfinamide(0.5 g, 2.18 mmol) in THF (7.5 mL) was added Cu(I) 2-thiophenecarboxylate (50 mg, 0.26 mmol), 2,6-Lutidine (1.3 ml, 11.16 mmol), andCyclopropyl azide (17% in MTBE, 1 ml, 7.82 mmol). The resulting solutionwas stirred at 40° C. (external) for 18 h and then diluted with EtOAc.The solution was washed with H2O and twice with aqueous NH4Cl. Theaqueous layers were back-extracted with EtOAc and the combined organiclayers were dried over MgSO4 and concentrated. The crude residue waspurified by SiO2 chromatography (15-50% EtOAc/CH2Cl2) to provide thedesired product.

1H NMR (400 MHz, Chloroform-d) δ 8.78 (d, J=1.2 Hz, 1H), 8.26 (s, 1H),1.82-1.75 (m, 2H), 1.72 (dt, J=8.0, 4.9 Hz, 2H), 1.26 (d, J=1.2 Hz, 9H).

ES/MS: 309.100 (M+H⁺).

To a solution of 3-bromo-6-fluoro-2-methylpyridine (370 mg, 1.95 mmol)in MeTHF (7.5 mL) at −78° C. (external). An n-Butyllithium solution (2.5M in hexanes, 1.25 ml) was added dropwise and the reaction was stirredat −78° C. for 1.5 h. To the yellow/orange solution was added(S,E)-2-methyl-N-((1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methylene)propane-2-sulfinamide(200 mg, 0.65 mmol) in MeTHF (2 mL), and the resulting solution waswarmed to room temperature for 2 h. The reaction was diluted with 50%NH4Cl and extracted twice with EtOAc. The combined organic layers weredried over Na2SO4 and concentrated. The crude material was purified bySiO2 chromatography (25-60% EtOAc(5% MeOH)/CH2Cl2) to provide thedesired product as a single isomer.

1H NMR (400 MHz, Chloroform-d) δ 7.91-7.81 (m, 1H), 7.52 (s, 1H), 6.81(dd, J=8.5, 3.3 Hz, 1H), 5.93 (d, J=3.4 Hz, 1H), 4.41 (d, J=3.5 Hz, 1H),2.55 (s, 3H), 1.74-1.59 (m, 4H), 1.24 (d, J=0.8 Hz, 9H).

ES/MS: 420.099 (M+H⁺).

A solution of(S)—N—((S)-(6-fluoro-2-methylpyridin-3-yl)(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)-2-methylpropane-2-sulfinamide(0.1 g, 0.25 mmol) in THF (3 mL) was cooled to 0° C. Sodium hydride (60%dispersion in mineral oil, 0.01 g, 0.29 mmol) was added and stirred for30 min before iodomethane was added (0.02 mL, 0.32 mmol). The resultingsolution was stirred at room temperature for 24 h and diluted withEtOAc. The solution was washed with 50% NH4Cl and the aqueous solutionwas back-extracted with EtOAc. The combine organic layers were driedover Na2SO4 and concentrated. The crude residue was purified by SiO2chromatography (20-50-60% EtOAc (5% MeOH)/CH2Cl2) to provide the desiredproduct.

1H NMR (400 MHz, Chloroform-d) δ 7.95 (t, J=8.2 Hz, 1H), 7.78 (s, 1H),6.83 (dd, J=8.5, 3.3 Hz, 1H), 5.99 (s, 1H), 2.58 (s, 3H), 2.46 (s, 3H),1.63 (d, J=62.7 Hz, 4H), 1.17 (s, 9H).

ES/MS: 433.820 (M+H⁺).

To a solution of(S)—N—((S)-(6-fluoro-2-methylpyridin-3-yl)(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)-N,2-dimethylpropane-2-sulfinamide(0.07 g, 0.17 mmol) in MeOH (1 mL) was added 4M HCl in dioxane (0.45ml). The resulting solution was stirred at room temperature for 2 h andconcentrated. The crude residue was diluted with EtOAc and washed withaqueous bicarbonate. The aqueous layer was back-extracted with EtOAc andthe combine organic layers were dried over Na2SO4 and concentrated. Thecrude amine was dissolved in a 1:1 mixture of CH2Cl2 and toluene andconcentrated to dryness to provide the desired product.

ES/MS: 329.872 (M+H⁺).

To a solution of(S)-1-(6-fluoro-2-methylpyridin-3-yl)-N-methyl-1-(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methanamine(0.05 g, 0.17 mmol) in toluene (3.5 mL) was added8-chloro-6-iodo-4-(neopentylamino)quinoline-3-carbonitrile (0.07 g, 0.17mmol), 2-(di-t-butylphosphino)biphenyl (0.02 g, 0.07 mmol), andtris(dibenzylideneacetone)dipalladium (O) (0.03 g, 0.03 mmol). Theslurry was degassed with argon for 5 min and potassium tert-butoxide,95% (0.06 g, 0.5 mmol) was added. The resulting slurry was heated to 80°C. (external) for 2 h. The reaction mixture was then diluted with EtOAcand washed with aqueous bicarbonate. The aqueous layers wereback-extracted and the resulting organic layers were concentrated. Thecrude oil was then purified by reverse-phase HPLC (10-70% MeCN/H2O with0.1% TFA). The product was purified a second time by reverse-phase HPLC(10-65% MeCN/H2O with 0.1% TFA) to provide the desired product as a TFAsalt.

1H NMR (400 MHz, Methanol-d4) δ 8.55 (d, J=1.6 Hz, 1H), 8.32 (s, 1H),7.88 (d, J=2.6 Hz, 1H), 7.59 (t, J=8.1 Hz, 1H), 7.40 (d, J=2.6 Hz, 1H),6.92 (dd, J=8.5, 2.8 Hz, 1H), 6.76 (s, 1H), 4.09 (d, J=14.1 Hz, 1H),3.96 (d, J=14.1 Hz, 1H), 2.97 (s, 3H), 2.35 (s, 3H), 1.80-1.70 (m, 4H),1.02 (d, J=3.2 Hz, 9H).

ES/MS: 601.367 (M+H⁺).

Example 49 Procedure 49(S)-8-acetyl-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

To(S)-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-8-iodo-4-(neopentylamino)quinoline-3-carbonitrile(37 mg, 0.056 mmol) and bis(triphenylphosphine)palladium(II) dichloride(5 mg, 0.006 mmol) in toluene (1 mL) was addedtributyl(2-ethoxyallyl)stannane (23 mg, 0.062 mmol). The reactionmixture was flushed with nitrogen and heated at 100° C. overnight. Aftercooling to room temperature, 2N HCl (1 mL) was added and the mixturestirred for 2 hours. Reaction was diluted with water and extractedthrice with EtOAc. Combined organics were washed with water and brineand dried (Na₂SO₄). Filtrate was concentrated to yield the crudematerial which was purified twice by HPLC (eluent: water/MeCN*0.1% TFA)to give the product.

The following compounds were prepared according to the Examples andProcedures described herein (and indicated in Table 1 underExample/Procedure) using the appropriate starting material(s) andappropriate protecting group chemistry as needed.

Lengthy table referenced here US20170008905A1-20170112-T00001 Pleaserefer to the end of the specification for access instructions.

Proton NMR data for select compounds shown below in Table 2.

TABLE 2 Compound ¹H-NMR 1 1H NMR (400 MHz, DMSO-d6) δ 8.37 (m, 2H), 8.17(s, 1H), 8.05 (m, 1H), 7.79 (brs, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.51(br s, 1H), 7.15 (m, 2H), 4.03 (m, 1H), 3.44 (dd, J = 13.9/5.5 Hz, 1H),1.59 (s, 9H), 0.88 (s, 9H). 2 1H NMR (400 MHz, CD3OD) δ 8.61 (m, 1H),8.37 (m, 1H), 8.29 (m, 1H), 8.05 (m, 1H), 7.73 (m, 1H), 7.60 (s, 1H),7.32 (m, 5H), 7.14 (m, 1H), 6.46 (s, 1H), 5.64 (m, 1H), 4.88 (m, 1H),2.83 (s, 3H), 2.17-2.02 (m, 2H), 1.56 (d, 6H), 0.97 (m, 3H). 3 1H NMR(400 MHz, CD3OD) δ 8.43 (m, 1H), 8.05 (m, 1H), 8.01 (m, 1H), 7.64 (m,1H), 7.42-7.25 (m, 6H), 6.98 (m, 1H), 5.80-5.66 (m, 1H), 3.97-3.84 (m,1H), 2.25-2.01 (m, 2H), 1.28-1.11 (m, 4H), 1.01 (m, 3H). 4 1H NMR (400MHz, DMSO-d6) δ 8.84 (dd, J = 14.0, 2.2 Hz, 1H), 8.64-8.52 (m, 1H), 8.23(d, J = 2.1 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 6.7 Hz, 1H),7.65-7.54 (m, 2H), 7.46 (d, J = 9.5 Hz, 1H), 7.43-7.38 (m, 1H),7.38-7.31 (m, 2H), 7.28-7.21 (m, 2H), 7.21-7.15 (m, 3H), 6.48 (d, J =6.9 Hz, 1H), 5.48 (q, J = 7.7 Hz, 1H), 5.35 (s, 0H), 4.68 (d, J = 2.0Hz, 2H), 4.50 (dd, J = 6.2, 4.5 Hz, 3H), 4.41 (dd, J = 6.7, 3.4 Hz, 2H),2.12 (dt, J = 14.5, 7.4 Hz, 1H), 2.04-1.78 (m, 1H), 0.94 (t, J = 7.3 Hz,3H), 0.85 (t, J = 7.2 Hz, 1H). 5 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s,1H), 8.47 (s, 1H), 8.14 (s, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.41-7.34 (m,2H), 7.27 (d, J = 8.2 Hz, 1H), 7.15 (dd, J = 9.1, 3.3 Hz, 2H), 7.12 (s,1H), 5.96 (d, J = 8.1 Hz, 1H), 4.50-4.32 (m, 1H), 3.00-2.83 (m, 2H),2.42-2.25 (m, 2H), 2.18-1.81 (m, 6H), 0.98 (t, J = 7.2 Hz, 3H). 6 1H NMR(400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.54 (dd, J= 5.0, 1.5 Hz, 1H), 8.41 (s, 1H), 8.13 (s, 1H), 8.00 (d, J = 8.0 Hz,1H), 7.67 (d, J = 2.2 Hz, 1H), 7.59-7.36 (m, 3H), 7.33-7.17 (m, 2H),6.20 (d, J = 8.0 Hz, 1H), 4.83-4.67 (m, 1H), 3.61 (d, J = 12.4 Hz, 2H),3.28-2.97 (m, 2H), 2.34 (d, J = 13.8 Hz, 2H), 2.17 (m, 2H), 1.22 (t, J =7.3 Hz, 2H). 9 1H NMR (400 MHz, Methanol-d4) δ 9.20 (s, 1H), 8.34 (s,1H), 8.05 (dd, J = 7.3, 1.9 Hz, 1H), 7.86 (d, J = 2.5 Hz, 1H), 7.82 (s,1H), 7.64-7.54 (m, 2H), 7.16 (d, J = 2.6 Hz, 1H), 6.34 (s, 1H), 3.97 (d,J = 13.7 Hz, 1H), 3.91-3.80 (m, 1H), 3.49 (d, J = 13.7 Hz, 1H),1.23-1.07 (m, 4H), 0.81 (s, 9H) 16 1H NMR (400 MHz, DMSO-d6) δ 8.92-8.83(m, 1H), 8.67 (d, J = 9.5 Hz, 1H), 8.65-8.58 (m, 1H), 8.24 (d, J = 3.3Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.64-7.56 (m, 2H), 7.52 (d, J = 8.3Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.39-7.29 (m, 2H), 7.29-7.16 (m, 6H),6.54 (d, J = 7.8 Hz, 1H), 5.47 (q, J = 7.6 Hz, 1H), 4.32 (t, J = 12.0Hz, 2H), 2.11 (m, 1H), 2.04-1.83 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H). 201H NMR (400 MHz, CD3OD) δ 9.02 (m, 1H), 8.46 (s, 1H), 8.01 (m, 1H), 7.68(m, 1H), 7.60 (m, 1H), 7.52 (m, 1H), 7.33 (m, 4H), 6.31 (s, 1H), 3.75(m, 2H), 3.25-3.13 (m, 3H), 2.45 (m, 2H), 2.36 (m, 2H), 2.25-2.01 (m,2H), 1.37 (m, 3H), 22 1H NMR (400 MHz, DMSO-d6) δ 8.49-8.38 (m, 1H),8.28 (d, J = 5.1 Hz, 1H), 8.13-8.02 (m, 2H), 7.84 (t, J = 2.4 Hz, 1H),7.65-7.52 (m, 2H), 7.42-7.31 (m, 1H), 7.31-7.15 (m, 4H), 5.49 (q, J =7.7 Hz, 1H), 4.04 (s, 3H), 3.20-3.11 (m, 1H), 2.20-2.05 (m, 1H),2.05-1.85 (m, 1H), 1.63-1.50 (m, 1H), 1.37-1.20 (m, 1H), 0.99-0.83 (m,3H) 23 1H NMR (400 MHz, Methanol-d4) δ 8.19 (s, 1H), 7.86 (s, 1H), 7.62(d, J = 2.5 Hz, 1H), 7.43-7.24 (m, 3H), 7.13 (d, J = 2.6 Hz, 1H), 6.05(s, 1H), 3.86-3.63 (m, 4H), 3.56 (d, J = 13.9 Hz, 1H), 3.39-3.29 (m,1H), 3.15-3.04 (m, 1H), 1.13-1.04 (m, 4H), 0.83 (s, 9H) 25 1H NMR (400MHz, Chloroform-d) δ 8.97 (s, 1H), 8.41 (s, 1H), 8.14 (d, J = 8.1 Hz,1H), 7.75 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H),7.15 (s, 1H), 6.50 (br s, 1H), 6.09 (br s, 1H), 3.67 (m, 1H), 3.59 (brs, 2H), 3.53-3.45 (m, 1H), 1.23-1.17 (m, 2H), 1.17-1.08 (m, 2H), 0.84(s, 9H) 27 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1H), 7.95 (s, 1H),7.62 (d, J = 2.3 Hz, 1H), 7.48 (dd, J = 7.1, 1.7 Hz, 1H), 7.45-7.37 (m,2H), 7.05 (d, J = 2.3 Hz, 1H), 6.08 (s, 1H), 4.86 (d, J = 14.7 Hz, 1H),4.57 (d, J = 1.7 Hz, 2H), 4.51 (d, J = 14.7 Hz, 1H), 4.12 (d, J = 13.9Hz, 1H), 3.94-3.84 (m, 1H), 3.73 (d, J = 13.9 Hz, 1H), 1.25-1.13 (m,4H), 0.95 (s, 9H) 36 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.08(s, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.58-7.50 (m, 1H), 7.43-7.34 (m, 2H),7.37-7.22 (m, 6H), 6.27 (s, 1H), 5.68 (t, J = 7.3 Hz, 1H), 4.92 (d, J =14.4 Hz, 1H), 4.61-4.49 (m, 3H), 2.27-2.19 (m, 1H), 2.12-2.02 (m, 1H),1.67 (s, 9H), 1.01 (t, J = 7.4 Hz, 2H) 61 1H NMR (400 MHz, Methanol-d4)δ 9.24 (s, 1H), 8.49 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 8.06 (d, J = 8.5Hz, 1H), 7.78 (s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.64 (dd, J = 8.4, 1.8Hz, 1H), 7.58-7.51 (m, 1H), 7.39-7.30 (m, 2H), 7.26 (d, J = 2.4 Hz, 1H),6.22 (s, 1H), 4.79 (m, 1H), 1.52 (dd, J = 6.7, 2.3 Hz, 6H) 62 1H NMR(400 MHz, Methanol-d4) δ 9.26 (s, 1H), 8.45 (s, 1H), 8.15 (s, 1H), 8.08(d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.64-7.56(m, 1H), 7.47 (dd, J = 6.5, 2.4 Hz, 1H), 7.35-7.21 (m, 3H), 6.24 (s,1H), 4.89-4.71 (m, 1H), 3.79 (d, J = 12.7 Hz, 2H), 3.20 (dd, J = 13.7,10.8 Hz, 2H), 2.42 (m, 4H), 1.45 (s, 9H) 63 1H NMR (400 MHz,Methanol-d4) δ 9.25 (s, 1H), 8.46 (s, 1H), 8.18 (d, J = 1.8 Hz, 1H),8.06 (d, J = 8.6 Hz, 1H), 7.85 (s, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.64(dd, J = 8.6, 1.8 Hz, 1H), 7.47 (dd, J = 6.4, 2.5 Hz, 1H), 7.35-7.20 (m,3H), 6.21 (s, 1H), 4.83-4.73 (m, 1H), 3.79 (d, J = 12.6 Hz, 2H),3.26-3.15 (m, 2H), 2.48-2.35 (m, 4H), 1.45 (s, 9H) 64 1H NMR (400 MHz,Methanol-d4) δ 8.44 (s, 1H), 7.95-7.84 (m, 2H), 7.77 (s, 1H), 7.69 (d, J= 2.4 Hz, 1H), 7.59 (d, J = 5.5 Hz, 1H), 7.50-7.39 (m, 2H), 7.35-7.19(m, 4H), 6.14 (s, 1H), 4.83-4.68 (m, 1H), 3.78 (d, J = 12.5 Hz, 2H),3.20 (t, J = 12.6 Hz, 2H), 2.52-2.30 (m, 4H), 1.45 (s, 9H) 71 1H NMR(400 MHz, Methanol-d4) δ 8.33 (s, 1H), 8.13-8.07 (m, 1H), 7.95-7.85 (m,2H), 7.55 (m, 1H), 7.36-7.18 (m, 7H), 5.91-5.79 (m, 1H), 3.82 m, 1H),2.59-2.46 (m, 2H), 2.50-2.22 (m, 2H), 1.20-1.02 (m, 4H). 72 1H NMR (400MHz, Methanol-d4) δ 8.43 (s, 1H), 7.92 (m, 1H), 7.85-7.72 (m, 1H), 7.60(m, 1H), 7.49-7.28 (m, 5H), 7.27-7.14 (m, 1H), 6.88 (m, 1H), 5.92 (m,1H), 3.90 (m, 1H), 2.66-2.50 (m, 5H), 2.43 (m, 2H), 1.28-1.10 (m, 4H).73 1H NMR (400 MHz, Methanol-d4) δ 8.45-8.33 (m, 2H), 8.01-7.87 (m, 2H),7.60 (m, 1H), 7.46-7.27 (m, 6H), 7.25 (m, 1H), 5.98-5.86 (m, 1H), 3.92(m, 1H), 2.67-2.33 (m, 4H), 1.29-1.12 (m, 4H). 74 1H NMR (400 MHz,Methanol-d4) δ 8.64 (m, 1H), 8.39 (m, 1H), 8.07 (s, 1H), 7.79 (m, 1H),7.60 (m, 1H), 7.41-7.29 (m, 6H), 6.46 (s, 1H), 5.86 (m, 1H), 3.93 (m,1H), 2.63 (m, 2H), 2.43 (m, 2H), 1.29-1.13 (m, 4H). 75 1H NMR (400 MHz,Methanol-d4) δ 8.83 (s, 1H), 8.70 (s, 1H), 8.43 (m, 1H), 8.38-8.28 (m,1H), 8.03 (m, 1H), 7.78 (m, 1H), 7.70-7.62 (m, 1H), 7.49-7.29 (m, 5H),6.43 (m, 1H), 6.00-5.89 (m, 1H), 2.66-1.98 (m, 4H), 1.25-1.13 (m, 4H).90 1H NMR (400 MHz, DMSO-d6) δ 8.21 (m, 1H), 8.09 (m, 1H), 7.60 (m, 1H),7.55-7.48 (m, 1H), 7.41-7.33 (m, 3H), 7.31 (d, J = 5.0 Hz, 2H),7.29-7.22 (m, 1H), 6.27 (d, J = 3.4 Hz, 1H), 5.66 (dd, J = 8.9, 5.5 Hz,1H), 4.82-4.64 (m, 4H), 4.56-4.41 (m, 1H), 3.96 (qd, J = 7.2, 4.2 Hz,1H), 3.00 (m, 1H), 2.82 (m, 1H), 2.62 (dd, J = 14.7, 7.5 Hz, 2H), 2.40(dt, J = 15.1, 7.4 Hz, 0H), 2.31 (d, J = 5.7 Hz, 0H), 2.29-2.17 (m, 1H),1.16-1.11 (m, 4H), 1.11 (s, 1H). 91 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s,1H), 8.05 (s, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.43 (s, 1H), 7.13 (s, 1H),6.11 (s, 1H), 4.73 (dt, J = 8.0, 4.4 Hz, 4H), 4.59-4.45 (m, 1H), 3.93(tt, J = 7.6, 4.4 Hz, 1H), 3.00 (s, 1H), 2.77 (d, J = 15.6 Hz, 1H), 1.11(td, J = 2.8, 1.7 Hz, 3H), 1.09 (t, J = 2.0 Hz, 1H), 0.89 (s, 9H). 92 1HNMR (400 MHz, DMSO-d6) δ 8.35 (m, 1H), 8.29 (m, 1H), 8.06 (m, 1H), 7.98(m, 1H), 7.58 (m, 1H), 7.34 (m, 1H), 7.16 (m, 1H), 7.01 (m, 1H), 6.61(m, 1H), 4.32 (tt, m, 1H), 3.93 (m, 2H), 3.40 (m, 2H), 3.06 (m, 1H),2.02-1.67 (m, 1H), 1.20-1.02 (m, 4H), 0.91 m, 3H), 0.54 (m, 3H) 99 1HNMR (400 MHz, DMSO-d6) δ 8.38-8.30 (m, 2H), 8.08-7.98 (m, 2H), 7.82 (d,J = 2.4 Hz, 1H), 7.55 (t, J = 6.9 Hz, 2H), 7.41 (d, J = 2.5 Hz, 1H),7.16 (dd, J = 8.5, 2.7 Hz, 1H), 4.02 (s, 4H), 3.42 (dd, J = 14.0, 5.5Hz, 1H), 0.85 (s, 9H) 100 1H NMR (400 MHz, DMSO-d6) δ 8.45 (dd, J = 2.3,1.1 Hz, 1H), 8.42-8.34 (m, 1H), 8.20-8.05 (m, 2H), 7.97-7.84 (m, 2H),7.68-7.58 (m, 2H), 7.50-7.25 (m, 5H), 7.23-7.12 (m, 1H), 6.05-5.90 (m,1H), 4.03-3.92 (m, 1H), 3.42-3.17 (m, 2H), 1.23-1.05 (m, 4H) 101 1H NMR(400 MHz, Methanol-d4) δ 8.87 (d, J = 5.4 Hz, 1H), 8.47 (d, J = 4.4 Hz,1H), 7.97 (d, J = 6.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.50-7.27 (m,6H), 5.78 (t, J = 7.2 Hz, 1H), 3.96-3.84 (m, 1H), 2.43 (s, 3H),2.28-2.04 (m, 2H), 1.27-1.11 (m, 4H), 1.02 (t, J = 7.3 Hz, 3H). 102 1HNMR (400 MHz, Methanol-d4) δ 8.86 (s, 1H), 8.52 (s, 1H), 7.96 (s, 1H),7.62 (m, 1H), 7.12 (m, 1H), 4.03 (m 1H), 3.95-3.85 (m, 2H), 2.45 (s,3H), 1.26-1.07 (m, 4H), 0.99 (s, 9H). 103 1H NMR (400 MHz, Methanol-d4)δ 8.50 (m, 1H), 8.11-7.98 (m, 2H), 7.65 (m, 1H), 7.11-7.04 (m, 1H), 6.98(m, 1H), 4.08 (m, 1H), 3.96-3.78 (m, 2H), 1.27-1.11 (m, 4H), 0.97 (s,9H). 106 1H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.33 (d, J = 2.6Hz, 1H), 8.01 (ddd, J = 8.5, 7.5, 2.6 Hz, 1H), 7.93 (s, 1H), 7.63 (d, J= 2.3 Hz, 1H), 7.39-7.23 (m, 6H), 7.11-7.03 (m, 1H), 5.73 (s, 1H),3.95-3.85 (m, 1H), 1.28-1.11 (m, 4H) 109 1H NMR (400 MHz, Methanol-d4) δ8.42 (s, 1H), 8.33 (d, J = 2.6 Hz, 1H), 8.00 (ddd, J = 8.5, 7.5, 2.6 Hz,1H), 7.93 (s, 1H), 7.64 (t, J = 2.1 Hz, 1H), 7.42-7.25 (m, 6H), 7.07(dd, J = 8.5, 2.6 Hz, 1H), 3.90 (m, 1H), 1.26-1.11 (m, 4H) 110 1H NMR(400 MHz, Methanol-d4) δ 8.45 (m, 1H), 7.92 (m, 1H), 7.79 (m, 1H), 7.62(m, 1H), 7.43-7.26 (m, 5H), 7.21-7.11 (m, 1H), 6.87 (m, 1H), 5.73 (m,1H), 3.89 (m, 1H), 2.54 (s, 3H), 2.25-2.10 (m, 1H), 2.08 (m, 1H),1.27-1.09 (m, 4H), 0.98 (m, 3H). 111 1H NMR (400 MHz, Methanol-d4) δ8.51 (s, 1H), 7.93 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.6, 2.7 Hz, 1H), 4.02(m, 1H), 3.94-3.83 (m, 2H), 2.51 (s, 3H), 1.25-1.10 (m, 4H), 0.94 (s,9H). 112 1H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.30 (dt, J =2.6, 0.8 Hz, 1H), 8.00 (ddd, J = 8.5, 7.5, 2.6 Hz, 1H), 7.92 (s, 1H),7.65 (d, J = 2.3 Hz, 1H), 7.12-7.04 (m, 2H), 3.89 (m, 1H), 1.25-1.10 (m,4H), 0.97 (s, 9H) 116 1H NMR (400 MHz, DMSO-d6) δ 8.37-8.30 (m, 2H),8.13 (s, 1H), 8.03 (td, J = 8.2, 2.6 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H),7.61-7.50 (m, 2H), 7.38 (d, J = 2.5 Hz, 1H), 7.19-7.11 (m, 1H),4.01-3.91 (m, 2H), 3.42 (dd, J = 14.0, 5.5 Hz, 1H), 1.19-1.04 (m, 4H),0.85 (s, 9H) 117 1H NMR (400 MHz, DMSO-d6) δ 8.53-8.38 (m, 1H), 8.28 (d,J = 5.7 Hz, 1H), 8.20-8.03 (m, 2H), 7.83 (t, J = 2.5 Hz, 1H), 7.63-7.52(m, 3H), 7.42-7.14 (m, 6H), 5.54-5.44 (m, 1H), 4.03-3.93 (m, 1H),2.21-2.04 (m, 1H), 2.05-1.84 (m, 1H), 1.25-1.05 (m, 4H), 1.04-0.80 (m,3H) 119 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.44-8.29 (m, 2H),8.14 (s, 1H), 8.04 (td, J = 8.2, 2.6 Hz, 1H), 7.72 (s, 1H), 7.43-7.26(m, 2H), 7.21-7.12 (m, 1H), 7.08 (d, J = 2.2 Hz, 1H), 4.10 (dd, J =14.0, 8.0 Hz, 1H), 4.01-3.90 (m, 1H), 3.59-3.49 (m, 1H), 1.19-1.04 (m,4H), 0.89 (s, 9H) 120 1H NMR (400 MHz, DMSO-d6) δ 8.48-8.38 (m, 1H),8.37-8.30 (m, 1H), 8.18-8.03 (m, 2H), 7.76 (d, J = 8.7 Hz, 1H), 7.55 (s,1H), 7.43-7.14 (m, 8H), 5.56 (q, J = 8.1 Hz, 1H), 4.03-3.92 (m, 1H),2.23-2.05 (m, 1H), 1.98 (ddt, J = 20.7, 13.7, 7.0 Hz, 1H), 1.21-1.05 (m,4H), 1.00-0.83 (m, 3H) 125 1H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H),7.91 (s, 1H), 7.69-7.59 (m, 2H), 7.26 (m, 1H), 6.85 (m, 1H), 4.03 (d, J= 13.9 Hz, 1H), 3.95-3.84 (m, 1H), 3.78 (d, J = 13.9 Hz, 1H), 2.52 (s,3H), 1.26-1.10 (m, 4H), 0.92 (s, 9H). 126 1H NMR (400 MHz, Methanol-d4)δ 8.48 (s, 1H), 8.35 (dd, J = 4.8, 1.9 Hz, 1H), 7.96 (s, 1H), 7.88 (dd,J = 7.7, 1.9 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.39 (m, 1H), 6.96 (d, J= 2.3 Hz, 1H), 4.02 (m, 1H), 3.96-3.78 (m, 2H), 1.27-1.07 (m, 4H), 0.96(s, 9H). 131 1H NMR (400 MHz, Methanol-d4) δ 8.61 (m, 1H), 8.47 (s, 1H),8.26 (m, 1H), 8.04 (s, 1H), 7.71 (m, 1H), 7.62 (m, 1H), 6.96 (m, 1H),6.33 (s, 1H), 4.03-3.83 (m, 3H), 2.73 (s, 3H), 1.27-1.12 (m, 4H), 0.93(s, 9H). 132 1H NMR (400 MHz, Methanol-d4) δ 8.62 (m, 1H), 8.48 (s, 1H),8.28 (m, 1H), 8.05 (s, 1H), 7.73 (m, 1H), 7.63 (d, J = 2.4 Hz, 1H), 6.99(d, J = 2.4 Hz, 1H), 4.03-3.80 (m, 3H), 2.74 (s, 3H), 1.27-1.12 (m, 4H),0.94 (s, 9H). 142 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.30 (d,J = 2.5 Hz, 1H), 8.00 (ddd, J = 8.5, 7.5, 2.6 Hz, 1H), 7.92 (s, 1H),7.66 (d, J = 2.3 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.08 (dd, J = 8.4,2.4 Hz, 1H), 4.13 (d, J = 14.0 Hz, 1H), 3.89 (m, 1H), 3.82 (d, J = 14.0Hz, 1H), 1.25-1.10 (m, 4H), 0.98 (s, 9H) 143 1H NMR (400 MHz, DMSO-d6) δ9.52 (s, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.91 (d, J = 1.9 Hz, 1H), 8.48(s, 1H), 8.33 (t, J = 2.1 Hz, 1H), 8.14 (s, 1H), 7.99 (d, J = 12.5 Hz,2H), 7.67 (d, J = 2.3 Hz, 1H), 7.49 (s, 1H), 7.17 (d, J = 2.4 Hz, 1H),4.00-3.89 (m, 1H), 1.16-1.10 (m, 2H), 1.10-1.04 (m, 2H). 144 1H NMR (400MHz, Methanol-d4) δ 8.61 (m, 1H), 8.38 (m, 1H), 8.29 (m, 1H), 8.04 (m,1H), 7.71 (m, 1H), 7.59 (m, 1H), 7.38-7.27 (m, 5H), 7.18 (m, 1H), 5.66(m, 1H), 3.92 (m, 1H), 2.77 (s, 3H), 2.28-1.95 (m, 2H), 1.25-1.07 (m,4H), 1.03-0.92 (m, 3H). 155 1H NMR (400 MHz, Methanol-d4) δ 8.43 (d, J =1.0 Hz, 1H), 8.33 (d, J = 2.5 Hz, 1H), 8.00 (ddd, J = 8.5, 7.6, 2.6 Hz,1H), 7.94 (s, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.41-7.25 (m, 6H), 7.07(ddd, J = 8.5, 2.7, 0.7 Hz, 1H), 5.77 (t, J = 7.2 Hz, 1H), 3.95-3.83 (m,1H), 2.26-2.03 (m, 2H), 1.26-1.11 (m, 4H), 1.03 (t, J = 7.3 Hz, 3H) 1741H NMR (400 MHz, DMSO-d6) δ 8.86-8.82 (m, 1H), 8.59 (dd, J = 5.0, 1.6Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.18 (d, J = 5.4 Hz, 1H), 8.06 (d, J= 2.0 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.52(dd, J = 8.0, 4.9 Hz, 1H), 7.37 (dt, J = 9.7, 3.8 Hz, 3H), 7.35-7.28 (m,1H), 7.27-7.21 (m, 2H), 7.21-7.15 (m, 3H), 6.41 (t, J = 8.6 Hz, 1H),5.46 (q, J = 7.7 Hz, 1H), 4.72 (t, J = 7.4 Hz, 2H), 4.58 (dd, J = 7.8,5.1 Hz, 2H), 4.42-4.29 (m, 1H), 4.17 (s, 1H), 3.77 (3, 1H), 3.25 (m,1H), 2.70-2.55 (m, 2H), 2.18-2.03 (m, 1H), 2.03-1.82 (m, 1H), 0.93 (t, J= 7.3 Hz, 3H). 175 1H NMR (400 MHz, DMSO-d6) δ 8.87-8.79 (m, 1H),8.64-8.54 (m, 1H), 8.23 (s, 2H), 8.08 (d, J = 7.8 Hz, 1H), 7.58 (d, J =2.4 Hz, 1H), 7.57-7.53 (m, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.40 (d, J =8.6 Hz, 1H), 7.37-7.31 (m, 2H), 7.29-7.21 (m, 2H), 7.19 (dt, J = 4.5,3.3 Hz, 2H), 6.49 (d, J = 7.8 Hz, 1H), 5.79 (d, J = 2.0 Hz, 2H), 5.46(q, J = 7.5 Hz, 1H), 5.35 (s, 0H), 2.23-2.06 (m, 1H), 2.02-1.84 (m, 1H),0.93 (t, J = 7.2 Hz, 3H). 176 1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H),8.90 (s, 1H), 8.65 (s, 1H), 8.25 (s, 1H), 8.23-8.09 (m, 2H), 7.62 (dd, J= 3.7, 2.1 Hz, 2H), 7.47 (d, J = 8.6 Hz, 1H), 7.42-7.33 (m, 2H),7.30-7.16 (m, 4H), 6.50 (d, J = 6.5 Hz, 1H), 5.49 (q, J = 7.7 Hz, 1H),5.43-5.32 (m, 1H), 4.46 (t, J = 7.0 Hz, 2H), 3.55 (m, 2H), 3.22-3.09 (m,2H), 3.03-2.90 (m, 2H), 2.27-2.07 (m, 3H), 2.07-1.77 (m, 5H), 0.95 (t, J= 7.3 Hz, 3H) 177 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.67 (s,1H), 8.28-8.13 (m, 3H), 7.68 (s, 1H), 7.60 (dd, J = 4.8, 2.1 Hz, 1H),7.56-7.43 (m, 2H), 7.40-7.28 (m, 2H), 7.28-7.12 (m, 5H), 6.50 (d, J =5.9 Hz, 1H), 5.47 (q, J = 7.7 Hz, 1H), 4.86 (dd, J = 5.2, 4.1 Hz, 1H),4.78-4.63 (m, 3H), 2.11 (dt, J = 13.6, 7.5 Hz, 1H), 1.91 (ddp, J = 20.8,14.0, 7.3 Hz, 1H), 0.97-0.77 (m, 3H) 181 1H NMR (400 MHz, DMSO-d6) δ8.88 (dd, J = 10.1, 2.1 Hz, 1H), 8.64 (ddd, J = 15.1, 5.2, 1.5 Hz, 1H),8.25 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.22 (s, 2H), 8.20 (s, 1H), 7.66(dd, J = 8.1, 5.2 Hz, 1H), 7.60 (dd, J = 4.5, 2.1 Hz, 1H), 7.49 (s, 1H),7.43 (d, J = 8.9 Hz, 1H), 7.40-7.34 (m, 1H), 7.33 (s, 1H), 7.28-7.20 (m,3H), 7.18 (dt, J = 8.0, 1.8 Hz, 2H), 6.50 (d, J = 5.7 Hz, 1H), 5.48 (q,J = 7.6 Hz, 1H), 5.05 (dtd, J = 18.1, 7.0, 4.2 Hz, 1H), 4.83-4.72 (m,1H), 4.72-4.59 (m, 1H), 2.21-2.06 (m, 1H), 2.04-1.85 (m, 1H), 1.49 (d, J= 8.0 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). 189 1H NMR (400 MHz, DMSO-d6) δ9.61 (s, 1H), 8.80 (s, 3H), 8.49 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 8.17(s, 1H), 8.09-7.98 (m, 2H), 7.81 (s, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.65(d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 6.33 (d, J = 6.4 Hz, 1H),4.87 (dd, J = 5.2, 4.0 Hz, 1H), 4.79-4.63 (m, 3H) 190 1H NMR (400 MHz,DMSO-d6) δ 8.84 (dd, J = 14.0, 2.2 Hz, 1H), 8.64-8.52 (m, 1H), 8.23 (d,J = 2.1 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 6.7 Hz, 1H),7.65-7.54 (m, 2H), 7.46 (d, J = 9.5 Hz, 1H), 7.43-7.38 (m, 1H),7.38-7.31 (m, 2H), 7.28-7.21 (m, 2H), 7.21-7.15 (m, 3H), 6.48 (d, J =6.9 Hz, 1H), 5.48 (q, J = 7.7 Hz, 1H), 5.35 (s, 0H), 4.68 (d, J = 2.0Hz, 2H), 4.50 (dd, J = 6.2, 4.5 Hz, 3H), 4.41 (dd, J = 6.7, 3.4 Hz, 2H),2.12 (dt, J = 14.5, 7.4 Hz, 1H), 2.04-1.78 (m, 1H), 0.94 (t, J = 7.3 Hz,3H), 0.85 (t, J = 7.2 Hz, 1H). 191 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s,1H), 8.67 (s, 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H),8.17 (d, J = 6.2 Hz, 1H), 7.67 (dt, J = 7.5, 3.2 Hz, 1H), 7.59 (dd, J =4.1, 2.1 Hz, 1H), 7.44 (t, J = 8.1 Hz, 2H), 7.40-7.30 (m, 1H), 7.29 (d,J = 2.3 Hz, 1H), 7.26-7.20 (m, 2H), 7.20-7.13 (m, 3H), 6.45 (d, J = 4.9Hz, 1H), 5.47 (q, J = 7.6 Hz, 1H), 4.03-3.92 (m, 1H), 2.18-2.02 (m, 1H),2.02-1.82 (m, 1H), 1.18-1.13 (m, 2H), 1.13-1.10 (m, 2H), 0.93 (t, J =7.3 Hz, 3H). 192 1H NMR (400 MHz, DMSO-d6) δ 8.89 (dd, J = 10.6, 2.1 Hz,1H), 8.65 (ddd, J = 15.0, 5.2, 1.5 Hz, 1H), 8.24 (dd, J = 6.1, 3.6 Hz,3H), 7.72-7.65 (m, 1H), 7.60 (dd, J = 4.3, 2.1 Hz, 1H), 7.52-7.38 (m,2H), 7.30 (d, J = 2.3 Hz, 1H), 7.28-7.19 (m, 3H), 7.16 (dq, J = 5.6, 1.6Hz, 2H), 6.47 (m, 1H), 5.49 (q, J = 7.6 Hz, 1H), 5.35 (q, J = 7.5 Hz,0H), 2.11 (dq, J = 15.3, 7.6 Hz, 1H), 1.92 (ddq, J = 21.0, 14.1, 7.2 Hz,1H), 1.59 (d, J = 1.0 Hz, 9H), 0.94 (t, J = 7.3 Hz, 3H). 193 1H NMR (400MHz, DMSO-d6) δ 8.87 (d, J = 11.9 Hz, 1H), 8.64 (d, J = 5.1 Hz, 1H),8.23 (d, J = 2.6 Hz, 1H), 8.21-8.13 (m, 2H), 7.63 (dd, J = 8.0, 5.1 Hz,1H), 7.60 (dd, J = 4.0, 2.2 Hz, 1H), 7.41 (dd, J = 15.7, 7.3 Hz, 2H),7.38-7.33 (m, 1H), 7.33-7.27 (m, 1H), 7.27-7.20 (m, 2H), 7.20-7.14 (m,2H), 6.48 (s, 1H), 5.48 (q, J = 7.6 Hz, 1H), 4.80 (h, J = 6.7 Hz, 1H),2.11 (dq, J = 14.8, 7.3 Hz, 1H), 2.00-1.85 (m, 1H), 1.47 (d, J = 8.0 Hz,6H), 0.94 (t, J = 7.3 Hz, 3H). 194 1H NMR (400 MHz, DMSO-d6) δ 8.93-8.83(m, 1H), 8.64 (ddd, J = 14.7, 5.1, 1.5 Hz, 1H), 8.36 (d, J = 7.0 Hz,1H), 8.25 (d, J = 1.5 Hz, 1H), 8.23-8.16 (m, 1H), 7.65 (dd, J = 8.0, 5.1Hz, 1H), 7.60 (dd, J = 4.0, 2.2 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H),7.41-7.33 (m, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.29-7.20 (m, 2H),7.20-7.14 (m, 2H), 6.51 (d, J = 5.6 Hz, 1H), 5.83 (tt, J = 7.6, 6.0 Hz,1H), 5.52-5.44 (m, 1H), 4.99 (ddd, J = 7.7, 6.8, 0.8 Hz, 2H), 4.88 (m,2H), 2.18-2.04 (m, 1H), 2.04-1.84 (m, 1H), 0.93 (t, J = 7.2 Hz, 2H). 1951H NMR (400 MHz, DMSO-d6) δ 8.86-8.83 (m, 1H), 8.60 (dd, J = 5.0, 1.6Hz, 1H), 8.26-8.21 (m, 1H), 8.20 (s, 1H), 8.10-8.04 (m, 1H), 7.59 (d, J= 2.3 Hz, 1H), 7.56 (dd, J = 8.0, 5.0 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H),7.45-7.37 (m, 1H), 7.37-7.31 (m, 2H), 7.26-7.16 (m, 6H), 6.55-6.44 (m,2H), 5.60-5.43 (m, 4H), 2.18-2.03 (m, 1H), 2.03-1.83 (m, 1H), 0.89 (t, J= 7.3 Hz, 3H). 212 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 27.8 Hz,2H), 8.28 (d, J = 7.1 Hz, 2H), 7.78-7.08 (m, 6H), 6.79 (s, 4H),5.59-5.33 (m, 1H), 4.92 (t, J = 6.8 Hz, 2H), 3.79 (t, J = 6.9 Hz, 2H),3.68-3.56 (m, 1H), 3.49-3.27 (m, 4H), 3.22-3.06 (m, 1H), 2.99 (d, J =2.4 Hz, 3H), 2.22-2.06 (m, 1H), 2.06-1.82 (m, 1H), 1.29-1.23 (m, 3H),1.17 (t, J = 7.1 Hz, 3H), 0.99-0.80 (m, 3H) 213 1H NMR (400 MHz,DMSO-d6) δ 8.31-8.16 (m, 3H), 7.72 (s, 1H), 7.61 (dd, J = 4.6, 2.1 Hz,1H), 7.53-7.43 (m, 2H), 7.43-7.13 (m, 7H), 6.55-6.44 (m, 1H), 5.49 (q, J= 7.6 Hz, 1H), 5.04-4.92 (m, 1H), 2.24-2.05 (m, 3H), 2.05-1.60 (m, 8H),1.29-1.20 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H) 221 1H NMR (400 MHz,Methanol-d4) δ 8.47 (s, 1H), 8.20 (m, 1H), 7.90 (s, 1H), 7.74 (m, 1H),7.66 (m, 1H), 7.52 (m, 1H), 7.45-7.32 (m, 2H), 7.32 (m, 1H), 7.27-7.20(m, 2H), 6.82 (d, J = 8.7 Hz, 1H), 6.05 (s, 1H), 4.91-4.77 (m, 1H), 3.89(s, 3H), 3.80 (m, 3H), 3.22 (m, 3H), 2.50-2.37 (m, 4H), 1.46 (s, 9H),1.43 (m, 3H). 223 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.18 (s,1H), 8.44 (s, 1H), 8.07 (s, 1H), 7.68 (d, J = 3.0 Hz, 1H), 7.62-7.50 (m,1H), 7.47-7.19 (m, 3H), 6.10 (d, J = 8.1 Hz, 1H), 4.75 (m, 5H), 3.62 (m,8H), 3.21-3.03 (m, 2H), 2.77 (m, 1H), 2.44-2.13 (m, 4H), 1.46-1.15 (m,9H). 237 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.21 (d, J = 2.0 Hz,1H), 8.14 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H),7.40 (s, 2H), 7.38-7.11 (m, 4H), 6.36 (d, J = 7.8 Hz, 1H), 5.81-5.70 (m,1H), 4.90-4.78 (m, 1H), 4.70 (m, 4H), 3.68 (d, J = 12.3 Hz, 3H), 3.14(d, J = 12.0 Hz, 3H), 2.44-2.24 (m, 5H), 1.68 (d, J = 6.7 Hz, 3H), 1.36(s, 9H). 238 1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J = 2.3 Hz, 1H), 7.84(d, J = 8.0 Hz, 1H), 7.63 (dd, J = 5.4, 2.1 Hz, 1H), 7.58 (d, J = 8.3Hz, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.34-7.26 (m, 4H), 7.23 (ddd, J =8.6, 5.2, 2.3 Hz, 2H), 6.38 (d, J = 6.3 Hz, 1H), 5.76 (q, J = 7.1 Hz,1H), 4.79-4.65 (m, 4H), 4.54-4.40 (m, 1H), 3.07-2.70 (m, 3H), 1.69 (d, J= 6.6 Hz, 3H). 241 1H NMR (400 MHz, DMSO-d6) δ 9.44 (d, J = 4.9 Hz, 1H),9.16 (s, 1H), 8.41 (s, 1H), 8.08 (s, 1H), 7.67 (s, 1H), 7.51 (t, J = 7.5Hz, 1H), 7.44-7.30 (m, 3H), 7.30-7.22 (m, 2H), 6.12 (d, J = 8.3 Hz, 1H),4.92 (s, 0H), 4.88-4.76 (m, 1H), 4.71 (s, 3H), 3.65 (d, J = 12.0 Hz,2H), 3.23-3.06 (m, 2H), 2.82 (s, 1H), 2.43-2.30 (m, 2H), 2.25 (d, J =13.8 Hz, 2H), 1.35 (s, 9H). 253 1H NMR (400 MHz, Methanol-d4) δ 8.87 (s,1H), 8.49 (s, 1H), 8.00 (s, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.47 (t, J =6.7 Hz, 1H), 7.35-7.18 (m, 3H), 6.34 (s, 1H), 4.84-4.76 (m, 1H), 3.80(d, J = 12.4 Hz, 2H), 3.27-3.16 (m, 2H), 2.53-2.36 (m, 4H), 2.42 (s,3H), 1.46 (s, 9H) 258 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.88 (d,J = 11.8 Hz, 1H), 8.63 (d, J = 15.9 Hz, 1H), 8.37-8.05 (m, 3H),7.68-7.10 (m, 10H), 6.49 (d, J = 7.0 Hz, 1H), 5.53-5.30 (m, 1H),4.95-4.74 (m, 1H), 3.69 (d, J = 11.8 Hz, 2H), 3.15 (q, J = 11.6 Hz, 2H),2.46-2.20 (m, 4H), 2.14 (dt, J = 14.4, 7.4 Hz, 1H), 1.94 (tt, J = 13.8,7.5 Hz, 1H), 1.37 (s, 9H), 1.10-0.76 (m, 3H) 264 1H NMR (400 MHz,Methanol-d4) δ 8.47 (s, 1H), 8.03 (s, 1H), 7.64 (d, J = 2.4 Hz, 1H),7.59-7.53 (m, 1H), 7.37-7.34 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 5.85 (s,1H), 5.37 (s, 1H), 4.84-4.74 (m, 1H), 4.14 (s, 2H), 3.81 (d, J = 12.4Hz, 2H), 3.77 (t, J = 5.6 Hz, 2H), 3.42 (s, 1H), 3.30-3.16 (m, 2H),2.50-2.35 (m, 4H), 2.18 (d, J = 17.4 Hz, 1H), 2.06 (d, J = 17.5 Hz, 1H),1.47 (s, 9H) 275 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.02 (d, J =15.9 Hz, 2H), 8.40 (s, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.50 (dd, J = 6.6,2.7 Hz, 1H), 7.43 (t, J = 9.0 Hz, 1H), 7.31 (s, 1H), 7.29 (d, J = 2.3Hz, 1H), 7.28-7.20 (m, 2H), 6.11 (d, J = 8.6 Hz, 1H), 4.31 (d, J = 5.2Hz, 2H), 3.33 (s, 2H), 2.88-2.72 (m, 1H), 2.72-2.56 (m, 1H). 279 1H NMR(400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.03 (s, 2H), 8.40 (s, 1H), 8.21 (s,1H), 7.66 (d, J = 2.2 Hz, 1H), 7.50 (dd, J = 6.5, 2.7 Hz, 1H), 7.44 (t,J = 9.0 Hz, 1H), 7.32 (s, 1H), 7.30 (t, J = 1.4 Hz, 1H), 7.29-7.24 (m,1H), 7.22 (d, J = 9.6 Hz, 2H), 6.11 (d, J = 8.6 Hz, 1H), 5.81 (tt, J =7.6, 6.0 Hz, 1H), 5.04-4.95 (m, 2H), 4.86 (ddd, J = 6.8, 6.0, 0.7 Hz,2H), 4.32 (m, 2H), 3.34 (m, 2H), 2.89-2.68 (m, 3H). 282 1H NMR (400 MHz,Methanol-d4) δ 8.66 (m, 1H), 8.49 (m, 2H), 8.09 (s, 1H), 7.87 (m, 1H),7.68 (m, 1H), 7.40 (m, 1H), 7.29-7.19 (m, 2H), 7.06 (m, 1H), 6.31 (s,1H), 4.97-4.86 (m, 1H), 2.69 (s, 3H), 1.56 (m, 6H). 283 1H NMR (400 MHz,Methanol-d4) δ 8.66 (m, 1H), 8.45 (m, 2H), 8.17 (s, 1H), 7.84 (m, 1H),7.67 (m, 1H), 7.39 (m, 1H), 7.38-7.19 (m, 2H), 7.09 (m, 1H), 6.34 (s,1H), 4.97-4.86 (m, 1H), 3.80 (m, 2H), 3.23 (m, 2H), 2.70 (s, 3H),2.48-2.41 (m, 4H), 1.46 (s, 9H). 301 1H NMR (400 MHz, DMSO-d6) δ 9.65(s, 1H), 8.46 (s, 1H), 8.05 (s, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.59 (dd,J = 6.6, 2.6 Hz, 1H), 7.50 (t, J = 9.0 Hz, 1H), 7.42 (d, J = 2.4 Hz,1H), 7.34 (ddd, J = 8.8, 4.2, 2.6 Hz, 1H), 7.20 (d, J = 22.3 Hz, 1H),6.78 (s, 1H), 6.07 (s, 1H), 4.83 (p, J = 6.7 Hz, 1H), 3.70 (t, J = 4.7Hz, 4H), 3.35 (dd, J = 6.1, 3.7 Hz, 4H), 1.49 (d, J = 8.0 Hz, 65H). 3021H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.47 (s, 1H), 8.23 (s, 1H),7.74 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 6.6, 2.6 Hz, 1H), 7.51 (t, J =9.0 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.35 (ddd, J = 8.6, 4.3, 2.6 Hz,1H), 6.80 (s, 1H), 6.12 (s, 1H), 5.94-5.83 (m, 1H), 5.02 (t, J = 7.3 Hz,2H), 4.92 (dt, J = 9.8, 6.6 Hz, 2H), 3.70 (t, J = 4.7 Hz, 4H), 3.35 (dd,J = 6.0, 3.7 Hz, 4H). 306 1H NMR (400 MHz, Methanol-d4) δ 8.89 (s, 1H),8.54 (s, 1H), 7.96 (s, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.63-7.55 (m, 1H),7.40-7.30 (m, 3H), 6.35 (s, 1H), 4.83 (m, 1H), 2.40 (s, 3H), 1.54 (dd, J= 6.7, 0.7 Hz, 6H) 307 1H NMR (400 MHz, Methanol-d4) δ 8.85 (s, 1H),8.49 (s, 1H), 7.99 (s, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.47 (dd, J = 6.4,2.5 Hz, 1H), 7.35-7.24 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 6.32 (s, 1H),4.82-4.75 (m, 1H), 3.81 (d, J = 12.7 Hz, 2H), 3.32-3.17 (m, 2H),2.51-2.38 (m, 4h), 2.40 (s, 3H), 1.46 (s, 9H) 308 1H NMR (400 MHz,DMSO-d6) δ 9.48 (s, 1H), 8.93-8.80 (m, 1H), 8.67 (dd, J = 5.2, 1.5 Hz,1H), 8.44 (s, 1H), 8.24 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), 7.82-7.65 (m,2H), 7.58 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 6.6, 2.6 Hz, 1H), 7.45 (t,J = 9.0 Hz, 1H), 7.34-7.24 (m, 2H), 6.32 (d, J = 7.4 Hz, 1H) 310 1H NMR(400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.90(s, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.63 (dd, J = 6.6, 2.4 Hz, 1H),7.46-7.34 (m, 3H), 6.11 (s, 1H), 1.65 (s, 9H) 311 1H NMR (400 MHz,Methanol-d4) δ 8.96 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 7.63 (d, J =2.4 Hz, 1H), 7.45 (d, J = 6.7 Hz, 1H), 7.41 (s, 1H), 7.35-7.18 (m, 3H),6.33 (s, 1H), 4.89-4.80 (m, 1H), 3.84 (s, 3H), 1.56 (d, J = 6.7 Hz, 6H)312 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.23 (s, 1H), 7.98 (s,1H), 7.90 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 6.4, 2.4 Hz,1H), 7.43-7.33 (m, 3H), 6.11 (s, 1H), 4.86-4.77 (m, 1H), 1.55 (d, J =6.8 Hz, 6H) 316 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.11 (d, J =1.9 Hz, 1H), 8.59-8.55 (m, 1H), 8.45 (s, 1H), 8.14 (s, 1H), 7.83 (td, J= 7.6, 1.8 Hz, 1H), 7.74 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H),7.65-7.59 (m, 1H), 7.57-7.44 (m, 2H), 7.43-7.32 (m, 2H), 7.30 (d, J =7.8 Hz, 1H), 6.43 (s, 1H), 5.74 (s, 2H). 317 1H NMR (400 MHz, DMSO-d6) δ9.53 (s, 1H), 8.56 (d, J = 5.0 Hz, 1H), 8.51 (d, J = 1.5 Hz, 1H), 8.49(d, J = 2.0 Hz, 1H), 8.27 (d, J = 1.7 Hz, 1H), 7.85 (td, J = 7.8, 2.0Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.67-7.56 (m, 2H), 7.54-7.43 (m, 3H),7.43-7.29 (m, 3H), 6.50 (d, J = 8.0 Hz, 1H), 5.77 (d, J = 1.9 Hz, 2H).331 1H NMR (400 MHz, Methanol-d4) δ 8.55 (m, 1H), 8.35 (m, 1H), 7.92 (s,1H), 7.89 (m, 1H), 7.68 (m, 1H), 7.57 (m, 1H), 7.41 (m, 1H), 7.36 (m,2H), 7.26 (m, 1H), 6.32 (s, 1H), 4.48 (m, 2H), 3.92 (m, 2H). 332 1H NMR(400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.48 (d, J = 1.1 Hz, 1H), 8.22 (d, J= 1.5 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.57 (dd, J = 6.5, 2.7 Hz, 1H),7.53-7.43 (m, 2H), 7.41 (d, J = 1.3 Hz, 1H), 7.33 (dt, J = 7.6, 3.4 Hz,1H), 6.49 (s, 1H), 4.84 (t, J = 6.7 Hz, 2H), 3.83 (s, 4H), 3.70 (t, J =6.7 Hz, 2H), 3.24 (d, J = 37.5 Hz, 4H). 333 1H NMR (400 MHz, DMSO-d6) δ9.51 (s, 1H), 8.50 (d, J = 1.4 Hz, 1H), 8.48 (s, 1H), 8.14 (s, 1H), 7.72(d, J = 2.2 Hz, 1H), 7.60 (dd, J = 6.8, 2.8 Hz, 2H), 7.56-7.46 (m, 2H),7.41 (s, 1H), 7.40-7.32 (m, 1H), 6.48 (d, J = 8.4 Hz, 1H), 4.45 (t, J =5.3 Hz, 2H), 3.81 (t, J = 5.3 Hz, 2H). 334 1H NMR (400 MHz, DMSO-d6) δ9.43 (s, 1H), 8.67 (s, 1H), 8.48 (d, J = 4.7 Hz, 1H), 8.40 (s, 1H), 7.98(d, J = 0.5 Hz, 1H), 7.86-7.80 (m, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.51(dd, J = 6.6, 2.6 Hz, 1H), 7.48-7.42 (m, 2H), 7.41-7.36 (m, 1H), 7.32(d, J = 2.4 Hz, 1H), 7.26 (ddd, J = 8.8, 4.2, 2.7 Hz, 1H), 6.29-6.07 (m,1H), 4.42 (t, J = 6.3 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 2.29 (s, 4H),1.48-1.21 (m, 6H) 336 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.69 (d,J = 2.3 Hz, 1H), 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (s, 1H), 8.02 (s,1H), 7.88-7.80 (m, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 6.6, 2.7Hz, 1H), 7.49 (d, J = 9.1 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.37 (ddd,J = 7.9, 4.8, 0.8 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.28 (dd, J = 7.9,4.4 Hz, 1H), 6.19 (d, J = 9.0 Hz, 1H), 5.09-4.99 (m, 1H), 4.38 (t, J =5.3 Hz, 2H), 3.82-3.68 (m, 2H) 337 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s,1H), 8.50 (d, J = 1.5 Hz, 1H), 8.48 (s, 1H), 8.13 (s, 1H), 7.72 (d, J =2.2 Hz, 1H), 7.65-7.58 (m, 2H), 7.53-7.45 (m, 2H), 7.43 (d, J = 1.4 Hz,1H), 7.34 (dt, J = 8.6, 3.4 Hz, 1H), 6.48 (d, J = 8.3 Hz, 1H), 4.57 (t,J = 5.1 Hz, 2H), 3.76 (t, J = 5.1 Hz, 2H), 3.24 (s, 2H). 338 1H NMR (400MHz, DMSO-d6) δ 9.59 (s, 1H), 8.50 (d, J = 2.2 Hz, 2H), 8.22 (d, J = 1.6Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.61 (dt, J = 6.5, 3.9 Hz, 2H), 7.50(dd, J = 9.8, 8.2 Hz, 1H), 7.46 (dd, J = 4.2, 2.1 Hz, 2H), 7.35 (ddd, J= 8.6, 4.3, 2.5 Hz, 1H), 6.46 (q, J = 2.4 Hz, 1H), 4.86 (p, J = 6.7 Hz,1H), 1.52 (d, J = 8.0 Hz, 6H). 339 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s,1H), 8.50 (d, J = 1.4 Hz, 1H), 8.48 (s, 1H), 8.39 (s, 1H), 7.71 (d, J =2.2 Hz, 1H), 7.66-7.55 (m, 2H), 7.54-7.42 (m, 3H), 7.34 (ddd, J = 8.6,4.1, 2.4 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 5.88 (tt, J = 7.3, 6.1 Hz,1H), 5.03 (t, J = 7.3 Hz, 2H), 4.93 (q, J = 6.3 Hz, 2H). 340 1H NMR (400MHz, DMSO-d6) δ 9.42 (s, 1H), 8.71-8.64 (m, 1H), 8.47 (dd, J = 4.8, 1.6Hz, 1H), 8.40 (s, 1H), 7.99 (d, J = 0.5 Hz, 1H), 7.84 (dt, J = 7.9, 1.9Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.52 (dd, J = 6.6, 2.6 Hz, 1H),7.50-7.41 (m, 2H), 7.38 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 7.31 (d, J =2.4 Hz, 1H), 7.27 (ddd, J = 8.9, 4.2, 2.7 Hz, 1H), 6.18 (d, J = 8.9 Hz,1H), 4.50 (t, J = 5.2 Hz, 2H), 3.77 (dd, J = 5.6, 4.8 Hz, 2H), 3.53-3.41(m, 2H), 3.36-3.24 (m, 2H), 3.13 (s, 3H) 342 1H NMR (400 MHz,Methanol-d4) δ 8.97 (s, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 7.64 (d, J =2.4 Hz, 1H), 7.51-7.39 (m, 2H), 7.39-7.25 (m, 3H), 6.36 (s, 1H),4.92-4.85 (m, 1H), 3.88 (s, 3H), 3.80 (d, J = 12.6 Hz, 2H), 3.29-3.18(m, 2H), 2.47 (m, 4H), 1.46 (s, 9H) 345 1H NMR (400 MHz, DMSO-d6) δ 9.92(s, 1H), 9.40 (d, J = 8.6 Hz, 1H), 8.40 (d, J = 3.4 Hz, 1H), 8.04 (d, J= 11.0 Hz, 1H), 7.66 (dd, J = 10.6, 2.2 Hz, 1H), 7.54-7.39 (m, 2H), 7.34(s, 1H), 7.31-7.18 (m, 3H), 6.08 (dd, J = 29.6, 8.6 Hz, 1H), 4.78 (p, J= 6.7 Hz, 1H), 4.57 (d, J = 15.6 Hz, 1H), 4.27 (s, 1H), 3.62 (s, 1H),3.27 (d, J = 12.0 Hz, 1H), 2.93 (s, 1H), 2.86 (d, J = 4.4 Hz, 3H), 2.80(s, 1H), 1.45 (d, J = 8.0 Hz, 6H). 346 1H NMR (400 MHz, DMSO-d6) δ 8.39(s, 1H), 8.01 (s, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 6.6, 2.7Hz, 1H), 7.43 (t, J = 9.0 Hz, 1H), 7.31 (s, 1H), 7.28-7.21 (m, 2H), 6.05(s, 1H), 4.76 (p, J = 6.7 Hz, 1H), 4.29 (s, 2H), 3.31 (dq, J = 22.6, 6.6Hz, 2H), 2.87-2.74 (m, 1H), 2.75-2.62 (m, 1H), 1.43 (d, J = 8.0 Hz, 6H).347 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1H), 8.28 (s, 1H), 8.02 (s,1H), 7.96 (s, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.47 (dd, J = 6.4, 2.5 Hz,1H), 7.43-7.24 (m, 2H), 7.20 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 8.6, 2.4Hz, 1H), 6.15 (s, 1H), 4.79 (d, J = 11.9 Hz, 1H), 3.80 (d, J = 12.6 Hz,2H), 3.22 (t, J = 12.5 Hz, 2H), 2.55-2.32 (m, 4H), 1.46 (s, 9H) 348 1HNMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H), 8.25-8.20 (m, 1H), 8.03 (s,1H), 7.92 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.53-7.46 (m, 1H),7.38-7.28 (m, 3H), 6.11 (s, 1H), 4.84-4.73 (m, 1H), 3.81 (d, J = 12.1Hz, 2H), 3.23 (t, J = 13.2 Hz, 2H), 2.51-2.35 (m, 4H), 1.46 (s, 9H) 3491H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 7.95-7.85 (m, 2H), 7.72(d, J = 2.0 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.59 (s, 1H), 7.43 (dd, J= 6.7, 2.3 Hz, 1H), 7.35 (dd, J = 8.6, 2.0 Hz, 1H), 7.31-7.18 (m, 3H),6.38 (s, 1H), 4.82-4.69 (m, 1H), 3.79 (d, J = 12.6 Hz, 2H), 3.20 (t, J =12.5 Hz, 2H), 2.57-2.29 (m, 5H), 1.45 (s, 9H) 350 1H NMR (400 MHz,Methanol-d4) δ 9.01 (d, J = 1.9 Hz, 1H), 8.49 (s, 1H), 7.95 (s, 1H),7.68 (d, J = 2.3 Hz, 1H), 7.62-7.52 (m, 2H), 7.50-7.39 (m, 1H),7.31-7.17 (m, 2H), 6.27 (s, 1H), 4.83-4.74 (m, 1H), 3.80 (d, J = 12.5Hz, 2H), 3.22 (t, J = 12.7 Hz, 2H), 2.74-2.14 (m, 4H), 1.46 (s, 9H) 3511H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 7.95-7.86 (m, 2H),7.75-7.65 (m, 2H), 7.55-7.46 (m, 2H), 7.40-7.26 (m, 5H), 6.45 (s, 1H),4.79 (m, 1H), 3.78 (d, J = 12.6 Hz, 2H), 3.25-3.14 (m, 2H), 2.47-2.31(m, 4H), 1.45 (s, 9H) 352 1H NMR (400 MHz, DMSO-d6) δ 9.06 (q, J = 1.8Hz, 1H), 8.39 (s, 1H), 8.08 (s, 1H), 7.69 (dd, J = 2.5, 1.2 Hz, 1H),7.65 (d, J = 2.0 Hz, 1H), 7.56-7.51 (m, 1H), 7.44 (t, J = 9.0 Hz, 1H),7.39 (t, J = 1.9 Hz, 1H), 7.28 (m, 1H), 6.36 (s, 1H), 4.76 (t, J = 6.8Hz, 2H), 3.76 (m, 4H), 3.63 (t, J = 6.7 Hz, 2H), 3.17 (m, 4H). 353 1HNMR (400 MHz, Methanol-d4) δ 9.02 (d, J = 2.0 Hz, 1H), 8.46 (s, 1H),7.98 (s, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.65-7.50 (m, 2H), 7.38-7.30 (m,3H), 6.32 (s, 1H), 4.79 (m, 1H), 3.80 (d, J = 12.6 Hz, 2H), 3.28-3.17(m, 2H), 2.49 (d, J = 13.0 Hz, 2H), 2.40 (d, J = 12.4 Hz, 2H), 1.46 (s,9H) 354 1H NMR (400 MHz, Methanol-d4) δ 9.03 (d, J = 1.9 Hz, 1H), 8.46(s, 1H), 7.97 (s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 1.9 Hz,1H), 7.53 (dd, J = 5.7, 1.9 Hz, 1H), 7.37-7.30 (m, 3H), 6.31 (s, 1H),4.86-4.80 (m, 1H), 3.60-3.50 (m, 2H), 3.22 (t, J = 11.0 Hz, 2H), 2.40(d, J = 14.4 Hz, 2H), 2.34-2.24 (m, 2H) 355 1H NMR (400 MHz, DMSO-d6) δ10.02 (s, 1H), 9.68 (s, 1H), 9.08 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H),7.75-7.65 (m, 2H), 7.55 (dd, J = 6.6, 2.6 Hz, 1H), 7.51-7.39 (m, 2H),7.30 (ddd, J = 8.8, 4.2, 2.6 Hz, 1H), 6.39 (s, 1H), 4.78 (t, J = 6.6 Hz,2H), 3.59 (dd, J = 7.9, 5.3 Hz, 2H), 2.77 (s, 7H). 356 1H NMR (400 MHz,DMSO-d6) δ 9.52 (s, 1H), 9.05 (d, J = 1.9 Hz, 1H), 8.38 (s, 1H), 7.96(s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.55 (dd, J= 6.6, 2.6 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.29 (ddd, J = 8.8, 4.3,2.7 Hz, 1H), 6.40-6.33 (m, 1H), 4.36 (t, J = 5.4 Hz, 3H), 3.73 (t, J =5.4 Hz, 3H). 357 1H NMR (400 MHz, DMSO-d6) δ 9.54 (d, J = 2.1 Hz, 1H),9.05 (d, J = 1.9 Hz, 1H), 8.39 (s, 1H), 8.01 (s, 1H), 7.68 (d, J = 2.2Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.53 (dd, J = 6.6, 2.6 Hz, 1H), 7.44(t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.28 (ddd, J = 8.9, 4.2,2.7 Hz, 1H), 6.33 (s, 1H), 4.77 (p, J = 6.7 Hz, 1H), 1.44 (d, J = 1.9Hz, 3H), 1.43 (d, J = 1.9 Hz, 3H). 358 1H NMR (400 MHz, DMSO-d6) δ 9.52(s, 1H), 9.05 (d, J = 1.9 Hz, 1H), 8.38 (s, 1H), 7.95 (s, 1H), 7.69 (d,J = 2.2 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 6.6, 2.6 Hz,1H), 7.44 (t, J = 9.0 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.29 (ddd, J =8.9, 4.3, 2.7 Hz, 1H), 6.35 (s, 1H), 4.49 (t, J = 5.1 Hz, 2H), 3.68 (t,J = 5.2 Hz, 2H), 3.18 (s, 4H). 359 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s,1H), 9.07 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 7.93 (s, 3H),7.69 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 6.6,2.6 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.28(ddd, J = 8.9, 4.3, 2.7 Hz, 2H), 6.37 (s, 1H), 4.56 (t, J = 6.3 Hz, 2H),3.39-3.25 (m, 2H). 360 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.37(d, J = 10.0 Hz, 1H), 9.06 (d, J = 1.9 Hz, 1H), 8.38 (s, 1H), 8.03 (s,1H), 7.69 (d, J = 2.2 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.52 (dd, J =6.6, 2.6 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H),7.37-7.25 (m, 2H), 6.35 (d, J = 7.3 Hz, 1H), 4.40 (t, J = 7.1 Hz, 2H),3.14-2.97 (m, 2H), 2.75 (s, 3H), 2.74 (s, 3H), 2.15 (p, J = 7.3 Hz, 2H).361 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.04 (d, J = 1.9 Hz, 1H),8.40 (s, 1H), 8.07 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 2.1,0.6 Hz, 1H), 7.55 (dd, J = 6.6, 2.6 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H),7.39 (d, J = 2.4 Hz, 1H), 7.29 (m, 1H), 6.33 (s, 1H), 1.55 (s, 9H). 3621H NMR (400 MHz, DMSO-d6) δ 9.44-9.36 (m, 1H), 8.75-8.65 (m, 1H), 8.46(dd, J = 4.8, 1.6 Hz, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.92-7.80 (m,1H), 7.68 (d, J = 2.3 Hz, 1H), 7.50 (dd, J = 6.6, 2.6 Hz, 1H), 7.49-7.40(m, 2H), 7.37 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 7.29-7.23 (m, 2H), 6.13(d, J = 8.5 Hz, 1H), 4.53-4.37 (m, 1H), 2.92 (d, J = 10.6 Hz, 2H), 2.33(t, J = 7.1 Hz, 2H), 2.09-1.86 (m, 6H), 1.00 (t, J = 7.2 Hz, 3H). 363 1HNMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.06 (d, J = 2.0 Hz, 1H), 8.38(s, 1H), 8.20 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 1.9 Hz,1H), 7.54 (dd, J = 6.6, 2.6 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.40 (d,J = 2.3 Hz, 1H), 7.28 (ddd, J = 8.9, 4.3, 2.7 Hz, 1H), 6.37 (s, 1H),5.81 (tt, J = 7.6, 6.1 Hz, 1H), 4.96 (t, J = 7.3 Hz, 2H), 4.85 (q, J =6.6 Hz, 2H). 364 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 9.08 (d, J =2.0 Hz, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 7.68 (dd, J = 3.9, 2.1 Hz, 2H),7.55 (dd, J = 6.7, 2.7 Hz, 1H), 7.49-7.40 (m, 2H), 7.29 (ddd, J = 8.6,4.3, 2.7 Hz, 1H), 6.39 (s, 1H), 5.77 (s, 2H). 365 1H NMR (400 MHz,DMSO-d6) δ 9.38 (s, 1H), 8.42 (s, 1H), 8.19 (s, 1H), 7.66 (d, J = 2.2Hz, 1H), 7.57-7.49 (m, 3H), 7.45-7.37 (m, 2H), 7.26 (ddd, J = 8.8, 4.2,2.6 Hz, 1H), 7.16 (dt, J = 3.8, 1.1 Hz, 1H), 6.43 (d, J = 8.6 Hz, 1H),4.53-4.39 (m, 1H), 2.91 (d, J = 10.8 Hz, 2H), 2.33 (q, J = 6.9 Hz, 2H),2.13-1.98 (m, 4H), 1.93 (dq, J = 11.7, 4.0, 3.5 Hz, 2H), 0.98 (t, J =7.2 Hz, 3H). 369 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.70 (s, 1H),8.56-8.30 (m, 2H), 8.14 (s, 1H), 7.87 (dt, J = 8.0, 1.9 Hz, 1H), 7.68(d, J = 2.2 Hz, 1H), 7.61-7.31 (m, 4H), 7.25 (qd, J = 4.1, 2.6 Hz, 2H),6.12 (d, J = 8.4 Hz, 1H), 4.60-4.28 (m, 1H), 3.05 (d, J = 10.9 Hz, 2H),2.27-1.75 (m, 6H), 1.02 (s, 9H) 370 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s,1H), 9.03 (d, J = 0.8 Hz, 1H), 8.95 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H),7.87 (t, J = 0.8 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.60-7.41 (m, 4H),7.31 (dt, J = 8.8, 3.7 Hz, 1H), 6.51 (d, J = 8.7 Hz, 1H), 4.88-4.77 (m,1H), 3.67 (d, J = 12.1 Hz, 2H), 3.20-3.09 (m, 2H), 2.39 (d, J = 13.8 Hz,2H), 2.25 (t, J = 12.8 Hz, 2H), 1.36 (s, 9H), 1.30 (s, 1H) 371 1H NMR(400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.26 (s, 1H), 8.42 (s, 1H), 8.03 (s,1H), 7.64 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 3.4 Hz, 1H), 7.48-7.42 (m,2H), 7.39 (t, J = 9.0 Hz, 1H), 7.26-7.14 (m, 3H), 6.01 (d, J = 7.2 Hz,1H), 4.72 (ddt, J = 11.8, 8.1, 4.3 Hz, 1H), 3.59 (d, J = 12.3 Hz, 2H),3.24-2.97 (m, 4H), 2.35-2.28 (m, 2H), 2.26-2.06 (m, 2H), 1.22 (t, J =7.3 Hz, 3H). 372 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 2H), 8.44 (d, J =1.4 Hz, 1H), 8.43 (s, 1H), 8.17 (s, 1H), 7.66 (d, J = 2.2 Hz, 1H),7.58-7.47 (m, 2H), 7.47-7.37 (m, 4H), 7.27 (ddd, J = 8.9, 4.2, 2.7 Hz,1H), 6.42 (d, J = 7.4 Hz, 1H), 4.77 (tt, J = 11.8, 4.1 Hz, 1H),3.73-3.57 (m, 2H), 3.12 (tdd, J = 23.8, 18.1, 9.9 Hz, 4H), 2.42-2.28 (m,2H), 2.28-2.12 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H). 373 1H NMR (400 MHz,DMSO-d6) δ 9.53 (s, 3H), 9.03 (dd, J = 3.0, 0.8 Hz, 1H), 8.43 (s, 1H),8.20 (s, 2H), 7.88 (t, J = 0.8 Hz, 2H), 7.66 (d, J = 2.1 Hz, 2H),7.61-7.42 (m, 8H), 7.32 (ddd, J = 8.9, 5.6, 3.0 Hz, 2H), 6.54 (d, J =8.4 Hz, 2H), 4.84-4.72 (m, 2H), 3.63 (d, J = 12.3 Hz, 4H), 3.43 (s, 1H),3.17-3.00 (m, 8H), 2.36 (d, J = 14.6 Hz, 4H), 2.23 (q, J = 12.8 Hz, 5H),1.67 (ddt, J = 15.8, 11.1, 7.5 Hz, 4H), 0.92 (td, J = 7.3, 5.5 Hz, 6H).375 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.02 (d, J = 0.8 Hz, 1H),8.65 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H), 7.87 (t, J = 0.8 Hz, 1H), 7.66(d, J = 2.2 Hz, 1H), 7.57 (dd, J = 6.6, 2.6 Hz, 1H), 7.52-7.40 (m, 3H),7.35-7.26 (m, 1H), 6.51 (d, J = 8.6 Hz, 1H), 4.86-4.76 (m, 1H), 3.41 (d,J = 13.0 Hz, 2H), 3.12-3.02 (m, 2H), 2.28 (d, J = 13.5 Hz, 2H), 2.12 (d,J = 12.5 Hz, 2H) 381 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.29 (s,1H), 8.42 (s, 1H), 8.13 (s, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.52 (dd, J =6.6, 2.6 Hz, 1H), 7.46 (t, J = 1.5 Hz, 1H), 7.43 (t, J = 9.0 Hz, 2H),7.39 (d, J = 2.4 Hz, 1H), 7.27 (ddd, J = 8.8, 4.2, 2.7 Hz, 1H),7.04-6.97 (m, 1H), 6.35 (d, J = 8.3 Hz, 1H), 4.76 (tt, J = 11.9, 4.1 Hz,1H), 3.62 (d, J = 12.4 Hz, 2H), 3.26-2.99 (m, 4H), 2.44-2.29 (m, 2H),2.18 (ddt, J = 22.1, 13.3, 7.4 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H). 382 1HNMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.20 (s, 1H), 8.42 (s, 1H), 8.26(s, 0H), 8.13 (s, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 6.6, 2.6Hz, 1H), 7.48-7.37 (m, 4H), 7.26 (ddd, J = 8.8, 4.2, 2.7 Hz, 1H), 6.95(d, J = 3.8 Hz, 1H), 6.90 (dd, J = 3.9, 0.9 Hz, 1H), 6.31 (d, J = 8.4Hz, 1H), 4.84-4.66 (m, 1H), 3.62 (d, J = 12.7 Hz, 2H), 3.24-2.98 (m,4H), 2.36 (d, J = 13.3 Hz, 2H), 2.17 (dd, J = 14.6, 11.1 Hz, 2H), 1.23(t, J = 7.3 Hz, 3H). 385 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.64(s, 1H), 8.42 (s, 2H), 8.12 (s, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.51 (dd,J = 6.6, 2.6 Hz, 1H), 7.47-7.40 (m, 3H), 7.39 (d, J = 2.4 Hz, 1H), 7.26(ddd, J = 8.8, 4.2, 2.7 Hz, 1H), 7.00 (dd, J = 1.6, 0.9 Hz, 1H), 6.35(d, J = 8.4 Hz, 1H), 4.79 (tt, J = 11.0, 4.0 Hz, 1H), 3.39 (d, J = 13.0Hz, 2H), 3.06 (q, J = 11.9 Hz, 2H), 2.26 (d, J = 13.2 Hz, 2H), 2.19-2.01(m, 2H). 386 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.65 (s, 1H),8.42 (s, 2H), 8.12 (s, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.52 (dd, J = 6.6,2.6 Hz, 1H), 7.47-7.40 (m, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.26 (ddd, J =8.8, 4.2, 2.7 Hz, 1H), 6.95 (d, J = 3.8 Hz, 1H), 6.90 (dd, J = 3.8, 0.9Hz, 1H), 6.31 (d, J = 8.1 Hz, 1H), 4.78 (ddt, J = 11.0, 8.1, 4.1 Hz,1H), 3.39 (d, J = 12.7 Hz, 2H), 3.07 (q, J = 11.8 Hz, 2H), 2.26 (d, J =13.4 Hz, 2H), 2.20-2.02 (m, 2H). 387 1H NMR (400 MHz, DMSO-d6) δ 9.43(s, 1H), 8.61 (s, 1H), 8.47 (s, 1H), 8.37 (d, J = 18.2 Hz, 1H), 8.07 (s,1H), 7.64 (d, J = 2.2 Hz, 1H), 7.56 (d, J = 5.4 Hz, 1H), 7.44-7.32 (m,4H), 7.19-7.08 (m, 3H), 6.99 (d, J = 5.4 Hz, 1H), 6.22 (d, J = 7.2 Hz,1H), 4.76 (td, J = 11.2, 5.4 Hz, 1H), 3.37 (d, J = 13.4 Hz, 2H), 3.06(t, J = 11.6 Hz, 2H), 2.22 (d, J = 13.7 Hz, 2H), 2.09 (t, J = 12.2 Hz,2H). 389 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.33 (s, 1H), 8.47(s, 1H), 8.09 (s, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.56 (dd, J = 5.3, 2.1Hz, 1H), 7.42-7.33 (m, 4H), 7.13 (ddd, J = 8.7, 3.7, 2.3 Hz, 3H),7.01-6.96 (m, 1H), 6.22 (d, J = 6.6 Hz, 1H), 4.74 (ddt, J = 11.8, 8.2,4.1 Hz, 1H), 3.60 (d, J = 12.3 Hz, 2H), 3.15 (qt, J = 11.5, 5.3 Hz, 3H),3.04 (dd, J = 13.2, 10.0 Hz, 2H), 2.41-2.28 (m, 3H), 2.24-2.09 (m, 3H),1.22 (t, J = 7.3 Hz, 3H). 400 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H),8.80 (s, 1H), 8.60 (d, J = 5.1 Hz, 1H), 8.41 (s, 1H), 8.25-8.06 (m, 2H),7.74-7.57 (m, 2H), 7.56-7.14 (m, 8H), 6.86 (d, J = 6.5 Hz, 1H), 6.23 (d,J = 6.9 Hz, 1H), 5.25 (s, 1H), 5.04 (t, J = 9.8 Hz, 2H), 3.96-3.76 (m,1H), 3.67 (d, J = 10.2 Hz, 1H), 3.59-3.37 (m, 2H), 2.47-2.21 (m, 2H).401 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.12 (brs, 2H), 8.74 (d, J= 2.2 Hz, 1H), 8.53 (dd, J = 4.9, 1.6 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J= 6.3 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.66 (dd, J = 2.4, 1.3 Hz, 1H),7.56-7.36 (m, 4H), 7.35-7.18 (m, 2H), 6.24 (d, J = 8.2 Hz, 1H),5.49-5.31 (m, 1H), 3.75-3.56 (m, 2H), 3.36 (t, J = 6.9 Hz, 2H), 2.48 (m,1H), 2.36-2.19 (m, 1H). 402 1H NMR (400 MHz, DMSO-d6) δ 10.01 (brs, 1H),9.40 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.51 (dd, J = 5.0, 1.5 Hz, 1H),8.41 (s, 1H), 8.21 (dd, J = 14.2, 7.1 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H),7.66 (t, J = 2.1 Hz, 1H), 7.57-7.36 (m, 4H), 7.34-7.18 (m, 2H), 6.21 (d,J = 8.0 Hz, 1H), 5.58-5.32 (m, 1H), 3.95-3.49 (m, 3H), 3.38-3.14 (m,3H), 2.80-2.62 (m, 1H), 2.42-2.19 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H). 4031H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.94 (s, 1H), 8.74 (dd, J =2.3, 0.8 Hz, 1H), 8.62 (dd, J = 4.9, 1.6 Hz, 1H), 8.44 (s, 1H), 7.97(dt, J = 8.0, 1.9 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.56 (ddd, J = 8.0,4.9, 0.8 Hz, 1H), 7.47 (dd, J = 6.6, 2.7 Hz, 2H), 7.44-7.38 (m, 2H),7.26 (d, J = 2.4 Hz, 1H), 7.23 (ddd, J = 8.8, 4.2, 2.7 Hz, 1H), 6.13 (d,J = 7.9 Hz, 1H), 3.76 (s, 3H). 404 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s,1H), 8.76 (s, 1H), 8.63-8.48 (m, 1H), 8.40 (s, 1H), 8.16 (s, 1H), 8.05(d, J = 8.0 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.61-7.13 (m, 10H), 6.87(s, 2H), 6.19 (d, J = 7.7 Hz, 1H), 5.07 (s, 2H), 4.71 (m, 1H), 4.07 (d,J = 13.1 Hz, 2H), 3.00 (m, 2H), 2.02 (d, J = 12.5 Hz, 2H), 1.92-1.66 (m,2H). 405 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.81-8.64 (m, 2H),8.54 (dd, J = 5.0, 1.6 Hz, 1H), 8.41 (s, 2H), 8.14 (s, 1H), 8.02 (d, J =8.1 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.58-7.36 (m, 4H), 7.32-7.16 (m,2H), 6.22 (d, J = 7.9 Hz, 1H), 4.87-4.66 (m, 1H), 3.38 (d, J = 12.9 Hz,2H), 3.06 (q, J = 12.0 Hz, 2H), 2.33-2.18 (m, 2H), 2.18-1.98 (m, 2H).408 1H NMR (400 MHz, Methanol-d4) δ 9.20 (s, 1H), 8.43 (s, 1H),8.09-8.02 (m, 1H), 7.98 (s, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.67 (d, J =7.2 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.38(s, 1H), 4.21 (d, J = 13.9 Hz, 1H), 3.53 (d, J = 13.9 Hz, 1H), 1.87-1.74(m, 2H), 1.65-1.50 (m, 2H), 0.85 (s, 9H). 409 1H NMR (400 MHz,Methanol-d4) δ 9.20 (s, 1H), 8.33 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H),8.00 (s, 1H), 7.84 (d, J = 2.5 Hz, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.59(t, J = 7.8 Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H), 6.37 (s, 1H), 4.00 (d, J= 13.7 Hz, 1H), 3.42 (d, J = 13.7 Hz, 1H), 1.87-1.74 (m, 2H), 1.62-1.52(m, 2H), 0.80 (s, 9H). 410 1H NMR (400 MHz, Methanol-d4) δ 9.20 (s, 1H),8.35 (s, 1H), 8.04 (dd, J = 7.4, 1.8 Hz, 1H), 7.87 (d, J = 2.5 Hz, 1H),7.82 (s, 1H), 7.64-7.53 (m, 2H), 7.17 (d, J = 2.5 Hz, 1H), 6.34 (s, 1H),3.98 (d, J = 13.7 Hz, 1H), 3.97-3.80 (m, 1H), 3.50 (d, J = 13.7 Hz, 1H),1.23-1.07 (m, 4H), 0.81 (s, 9H). 411 1H NMR (400 MHz, Methanol-d4) δ9.20 (s, 1H), 8.23 (s, 1H), 8.10-8.03 (m, 1H), 7.86 (d, J = 2.5 Hz, 1H),7.83 (s, 1H), 7.69 (d, J = 7.3 Hz, 1H), 7.65-7.54 (m, 1H), 7.36-7.29 (m,1H), 7.21-7.11 (m, 2H), 6.92 (d, J = 6.8 Hz, 2H), 6.46 (s, 1H), 5.48 (t,J = 7.1 Hz, 1H), 3.90-3.84 (m, 1H), 2.05 (dt, J = 14.4, 7.2 Hz, 1H),1.84 (dt, J = 13.9, 7.1 Hz, 1H), 1.22-1.10 (m, 4H), 0.94 (t, J = 7.3 Hz,3H). 412 1H NMR (400 MHz, Methanol-d4) δ 9.20 (s, 1H), 8.24 (s, 1H),8.12 (s, 1H), 8.07 (dd, J = 8.1, 1.1 Hz, 1H), 7.88 (d, J = 2.6 Hz, 1H),7.71 (d, J = 7.3 Hz, 1H), 7.62-7.55 (m, 1H), 7.38-7.30 (m, 2H),7.23-7.10 (m, 2H), 6.96-6.89 (m, 2H), 6.53 (s, 1H), 5.49 (t, J = 7.0 Hz,1H), 2.06 (dt, J = 14.1, 7.1 Hz, 1H), 1.85 (dt, J = 14.1, 7.3 Hz, 1H),1.75-1.62 (m, 4H), 0.95 (t, J = 7.3 Hz, 3H). 413 1H NMR (400 MHz,Methanol-d4) δ 8.44 (s, 1H), 8.21 (s, 1H), 8.05 (m, 1H), 7.81 (t, J =8.1 Hz, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.44-7.29 (m, 5H), 7.24 (m, 1H),6.97-6.85 (m, 2H), 5.95 (m, 1H), 3.47 (m, 1H), 2.67-2.41 (m, 7H), 1.80(m, 4H). 414 1H NMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 7.99 (s, 1H),7.73 (m, 1H), 7.57 (m, 1H), 7.42 (s, 1H), 7.40-7.27 (m, 5H), 6.19 (s,1H), 5.76 (dd, J = 8.6, 5.5 Hz, 1H), 4.90 (td, J = 7.6, 3.1 Hz, 2H),4.78 (m, 2H), 4.55-4.35 (m, 5H), 3.92 (m, 1H), 2.91 (m, 1H), 2.63 (m,2H), 2.44 (m, 1H), 2.36 (m, 1H), 1.22 (m, 2H), 1.17 (m, 2H). 415 1H NMR(400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.47 (s, 1H), 8.14 (d, J = 0.6Hz, 1H), 8.06 (dd, J = 7.4, 1.8 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H),7.65-7.55 (m, 2H), 7.01 (d, J = 2.3 Hz, 1H), 6.40 (s, 1H), 4.17 (d, J =13.9 Hz, 1H), 3.60 (d, J = 13.8 Hz, 1H), 2.02-1.83 (m, 4H), 0.86 (s,9H). 416 1H NMR (400 MHz, Methanol-d4) δ 9.20 (s, 1H), 8.49 (s, 1H),8.05 (dd, J = 8.0, 1.1 Hz, 1H), 7.98 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H),7.67 (d, J = 7.1 Hz, 1H), 7.59 (dd, J = 8.1, 7.4 Hz, 1H), 7.01 (d, J =2.3 Hz, 1H), 6.39 (s, 1H), 4.24 (d, J = 13.9 Hz, 1H), 3.55 (d, J = 13.9Hz, 1H), 1.88-1.74 (m, 2H), 1.65-1.50 (m, 2H), 0.86 (s, 9H). 417 1H NMR(400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.47 (s, 1H), 8.10 (s, 1H), 8.06(dd, J = 7.3, 1.9 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.65-7.54 (m, 2H),7.02 (d, J = 2.3 Hz, 1H), 6.41 (s, 1H), 4.18 (d, J = 13.8 Hz, 1H), 3.60(d, J = 13.8 Hz, 1H), 1.79-1.59 (m, 4H), 0.86 (s, 9H). 418 1H NMR (400MHz, Methanol-d4) δ 9.21 (s, 1H), 8.47 (s, 1H), 8.05 (dd, J = 6.7, 2.5Hz, 1H), 7.80 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.63-7.54 (m, 2H), 6.99(d, J = 2.4 Hz, 1H), 6.35 (s, 1H), 4.17 (d, J = 13.9 Hz, 1H), 3.86 (ddd,J = 11.4, 7.3, 4.0 Hz, 1H), 3.60 (d, J = 13.8 Hz, 1H), 1.23-1.08 (m,4H), 0.85 (s, 9H). 419 1H NMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H),8.45 (s, 1H), 8.09-8.02 (m, 1H), 7.83 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H),7.64 (d, J = 7.4 Hz, 1H), 7.62-7.55 (m, 1H), 7.00 (d, J = 2.4 Hz, 1H),6.39 (s, 1H), 4.77 (td, J = 11.4, 5.5 Hz, 1H), 4.18 (d, J = 13.8 Hz,1H), 3.79 (d, J = 12.6 Hz, 2H), 3.55 (d, J = 13.8 Hz, 1H), 3.20 (t, J =12.0 Hz, 2H), 2.47-2.37 (m, 4H), 1.45 (s, 9H), 0.84 (s, 9H). 420 1H NMR(400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.28 (s, 1H), 8.06 (dd, J = 7.7,1.5 Hz, 1H), 7.82 (d, J = 2.2 Hz, 2H), 7.67-7.55 (m, 2H), 7.15 (d, J =2.5 Hz, 1H), 6.39 (d, J = 4.6 Hz, 1H), 4.79-4.71 (m, 1H), 3.90 (d, J =13.7 Hz, 1H), 3.80 (d, J = 12.5 Hz, 2H), 3.43 (d, J = 13.7 Hz, 1H),3.24-3.15 (m, 2H), 2.51-2.34 (m, 4H), 1.45 (s, 9H), 0.79 (s, 9H). 421 1HNMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.47 (s, 1H), 8.06 (dd, J =7.5, 1.8 Hz, 1H), 7.96 (s, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.65-7.54 (m,2H), 7.02 (d, J = 2.3 Hz, 1H), 6.40 (s, 1H), 5.92 (t, J = 54.7 Hz, 1H),4.18 (d, J = 13.9 Hz, 1H), 3.60 (d, J = 13.9 Hz, 1H), 1.54-1.46 (m, 4H),0.86 (s, 9H). 422 1H NMR (400 MHz, Methanol-d4) δ 8.51 (d, J = 5.8 Hz,2H), 7.95 (d, J = 2.4 Hz, 1H), 7.90 (s, 1H), 7.68 (d, J = 2.3 Hz, 1H),7.27 (dd, J = 7.0, 1.0 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.86 (t, J =7.0 Hz, 1H), 6.61 (dd, J = 2.4, 0.9 Hz, 1H), 6.33 (s, 1H), 4.10 (d, J =13.9 Hz, 1H), 3.87 (tt, J = 7.5, 4.1 Hz, 1H), 3.68 (d, J = 13.8 Hz, 1H),1.24-1.08 (m, 4H), 0.83 (s, 9H). 423 1H NMR (400 MHz, Methanol-d4) δ8.47 (s, 1H), 8.09 (d, J = 0.9 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J = 2.2Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 8.5, 7.1 Hz, 1H), 7.26(d, J = 7.0 Hz, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.43 (s, 1H), 4.15 (d, J= 13.9 Hz, 1H), 4.05 (s, 3H), 3.90-3.79 (m, 1H), 3.64 (d, J = 13.9 Hz,1H), 1.22-1.06 (m, 4H), 0.84 (s, 9H). 424 1H NMR (400 MHz, Methanol-d4)δ 9.21 (s, 1H), 8.35 (s, 1H), 8.05 (dd, J = 7.7, 1.6 Hz, 1H), 7.97 (s,1H), 7.88 (d, J = 2.5 Hz, 1H), 7.66-7.54 (m, 2H), 7.19 (d, J = 2.5 Hz,1H), 6.39 (s, 1H), 5.93 (t, J = 54.7 Hz, 1H), 3.99 (d, J = 13.7 Hz, 1H),3.49 (d, J = 13.8 Hz, 1H), 1.51-1.48 (m, 4H), 0.82 (s, 9H). 425 1H NMR(400 MHz, DMSO-d6) δ 8.40-8.35 (m, 2H), 8.08 (d, J = 0.8 Hz, 1H), 8.05(dd, J = 8.2, 2.6 Hz, 1H), 7.85 (s, 1H), 7.66-7.62 (m, 1H), 7.58 (s,1H), 7.23-7.17 (m, 2H), 5.32 (s, 2H), 4.04 (dd, J = 14.1, 8.0 Hz, 1H),3.48 (dd, J = 14.1, 5.6 Hz, 1H), 3.27 (d, J = 0.7 Hz, 3H), 0.88 (s, 9H).426 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.25 (s, 1H), 7.76 (s,1H), 7.69 (d, J = 2.2 Hz, 1H), 7.54 (dt, J = 8.6, 0.9 Hz, 1H), 7.25 (dd,J = 8.6, 6.9 Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 7.00 (d, J = 2.3 Hz,1H), 6.32 (s, 1H), 4.17 (s, 3H), 4.15 (d, J = 14.7 Hz, 1H), 3.89-3.79(m, 1H), 3.63 (d, J = 13.8 Hz, 1H), 1.21-1.05 (m, 4H), 0.84 (s, 9H). 4271H NMR (400 MHz, Methanol-d4) δ 8.33 (s, 1H), 7.85 (dd, J = 6.2, 2.8 Hz,2H), 7.80 (s, 1H), 7.56-7.44 (m, 2H), 7.14 (d, J = 2.5 Hz, 1H), 6.26 (s,1H), 3.98 (d, J = 13.7 Hz, 1H), 3.91-3.81 (m, 1H), 3.47 (d, J = 13.7 Hz,1H), 2.78 (s, 3H), 1.26-1.06 (m, 4H), 0.82 (s, 9H). 428 1H NMR (400 MHz,Methanol-d4) δ 8.22 (s, 1H), 7.99 (s, 1H), 7.75 (d, J = 2.5 Hz, 1H),7.63-7.56 (m, 1H), 7.44-7.39 (m, 2H), 7.37 (d, J = 2.5 Hz, 1H), 7.34 (d,J = 4.4 Hz, 1H), 7.31-7.21 (m, 2H), 7.15 (dd, J = 7.2, 2.5 Hz, 2H), 6.20(s, 1H), 5.51 (t, J = 7.0 Hz, 1H), 4.62-4.48 (m, 4H), 3.94-3.88 (m, 1H),2.20-1.89 (m, 2H), 1.23-1.17 (m, 4H), 0.99 (t, J = 7.4 Hz, 3H). 429 1HNMR (400 MHz, Methanol-d4) δ 8.30 (s, 1H), 8.25 (s, 1H), 7.72 (d, J =2.5 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J = 2.5 Hz, 1H), 6.15 (s, 1H), 4.91(m, 2H), 4.80 (m, 2H), 4.62-4.46 (m, 2H), 4.39 (m, 1H), 3.86 (d, J =13.9 Hz, 1H), 3.75 (d, J = 13.9 Hz, 1H), 3.52 (s, 1H), 3.48-3.36 (m,1H), 3.23-3.11 (m, 1H), 3.00-2.94 (m, 1H), 1.78 (m, 2H), 1.68 (3, 2H),0.98 (s, 9H). 430 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 8.09 (s,1H), 7.86 (td, J = 3.3, 2.2 Hz, 2H), 7.58-7.46 (m, 2H), 7.17 (d, J = 2.5Hz, 1H), 6.33 (s, 1H), 3.99 (d, J = 13.8 Hz, 1H), 3.47 (d, J = 13.7 Hz,1H), 2.77 (s, 3H), 1.79-1.57 (m, 4H), 0.83 (s, 9H). 431 1H NMR (400 MHz,Chloroform-d) δ 8.42 (s, 1H), 7.88 (m, 1H), 7.48-7.28 (m, 6H), 6.81 (m,1H), 6.76 (s, 1H), 5.97 (s, 1H), 5.67 (m, 1H), 5.30 (s, 2H), 3.73 (m,1H), 2.57 (s, 3H), 2.57-2.47 (m, 1H), 2.33 (m, 1H), 1.57 (s, 2H),0.92-0.81 (m, 4H). 432 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H),8.20 (s, 1H), 7.79 (m, 1H), 7.61 (m, 1H), 6.88 (m, 2H), 6.24 (s, 1H),3.88 (m, 2H), 3.62 (m, 2H), 2.51 (s, 3H), 1.86-1.56 (m, 4H), 0.92 (s,9H). 433 1H NMR (400 MHz, Methanol-d4) δ 8.30 (s, 1H), 7.96 (s, 1H),7.71 (d, J = 2.5 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J = 2.5 Hz, 1H), 6.07(s, 1H), 4.92 (m, 2H), 4.82-4.78 (m, 2H), 4.64-4.47 (m, 2H), 4.40 (m,1H), 3.90 (m, 1H), 3.85 (d, J = 14.1 Hz, 1H), 3.76 (d, J = 13.9 Hz, 1H),3.52 (m, 1H), 3.42 (m, 1H), 3.16-3.13 (m, 1H), 3.02-2.88 (m, 1H),1.24-1.13 (m, 4H), 0.98 (s, 9H). 434 1H NMR (400 MHz, Methanol-d4) δ9.21 (s, 1H), 8.46 (s, 1H), 8.05 (dd, J = 7.0, 2.2 Hz, 1H), 7.87 (s,1H), 7.72 (d, J = 2.3 Hz, 1H), 7.64-7.54 (m, 2H), 6.98 (d, J = 2.3 Hz,1H), 6.35 (s, 1H), 4.17 (d, J = 13.8 Hz, 1H), 3.58 (d, J = 13.8 Hz, 1H),1.63 (s, 3H), 1.32-1.25 (m, 2H), 1.08-1.00 (m, 2H), 0.84 (s, 9H). 435 1HNMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.35 (s, 1H), 8.05 (dd, J =7.5, 1.7 Hz, 1H), 7.89 (s, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.65-7.54 (m,2H), 7.16 (d, J = 2.5 Hz, 1H), 6.35 (s, 1H), 4.00 (d, J = 13.7 Hz, 1H),3.49 (d, J = 13.8 Hz, 1H), 1.63 (s, 3H), 1.31-1.25 (m, 2H), 1.08-0.99(m, 2H), 0.81 (s, 9H). 436 1H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H),8.02-7.93 (m, 2H), 7.62 (m, 1H), 7.07 (m, 1H), 6.96 (m, 1H), 6.31 (s,1H), 4.12-3.98 (m, 1H), 3.95-3.80 (m, 1H), 3.39 (m, 1H), 1.29-1.10 (m,2H), 1.03 (s, 2H), 0.97 (s, 9H). 4.94-4.85 (m, 4H), 4.87 (s, 21H), 4371H NMR (400 MHz, Methanol-d4) δ 9.01 (m, 1H), 8.83 (d, J = 8.6 Hz, 1H),8.49 (s, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.90-7.81 (m, 2H), 7.81-7.65 (m,4H), 6.92 (d, J = 2.3 Hz, 1H), 6.84 (s, 1H), 4.01 (d, J = 13.9 Hz, 1H),3.86 (m, 1H), 3.62 (d, J = 13.9 Hz, 1H), 1.22-1.07 (m, 4H), 0.70 (s,9H). 438 1H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 1H), 7.90 (m, 1H),7.43-7.26 (m, 5H), 7.22 (m, 2H), 6.78 (m, 1H), 6.61 (s, 1H), 6.00 (s,1H), 5.69 (m, 1H), 5.30 (s, 2H), 3.75 (m, 3.8 Hz, 1H), 2.65 (s, 3H),2.64-2.49 (m, 1H) 2.44 (s, 2H), 2.33 (s, 1H), 0.92-0.81 (m, 4H). 440 1HNMR (400 MHz, Methanol-d4) δ 8.45 (m, 1H), 8.21 (s, 1H), 7.82 (m, 1H),7.64 (m, 1H), 7.40-7.25 (m, 5H), 7.13 (m, 1H), 6.93-6.83 (m, 1H), 6.37(m, 1H), 5.79-5.64 (m, 1H), 2.53 (m, 3H), 2.23-2.09 (m, 1H), 2.07 (m,1H), 1.81-1.64 (m, 4H), 1.04-0.91 (m, 3H) 441 1H NMR (400 MHz, DMSO-d6)δ 9.32 (s, 1H), 8.30 (d, J = 1.5 Hz, 1H), 8.16 (s, 1H), 8.00 (dd, J =8.1, 1.2 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.69-7.57 (m, 2H), 7.50 (td,J = 7.8, 1.5 Hz, 1H), 7.43-7.30 (m, 2H), 6.46 (d, J = 5.8 Hz, 1H), 4.72(s, 1H), 4.60 (s, 1H), 3.87 (dd, J = 13.8, 8.1 Hz, 1H), 3.34 (dd, J =13.8, 5.0 Hz, 1H), 1.41-1.27 (m, 4H), 0.75 (s, 9H). 443 1H NMR (400 MHz,Methanol-d4) δ 9.75 (s, 1H), 8.59 (m, 1H), 8.46 (s, 1H), 8.26 m, 1H),8.13 (m, 1H), 8.01-7.86 (m, 3H), 7.68 (m, 1H), 6.96 (m, 2H), 4.05-3.96(m, 1H), 3.87 (m, 1H), 3.63 (m, 1H), 1.37 (m, 1H), 1.21-1.07 (m, 4H),0.72 (s, 9H). 444 1H NMR (400 MHz, Methanol-d4) δ 8.50 (d, J = 7.0 Hz,1H), 8.37 (s, 1H), 8.06 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.83 (d, J =2.5 Hz, 1H), 7.29 (dt, J = 7.0, 1.0 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H),6.87 (t, J = 7.0 Hz, 1H), 6.64 (dd, J = 2.4, 0.9 Hz, 1H), 6.38 (s, 1H),5.93 (t, J = 54.8 Hz, 1H), 3.93 (d, J = 13.8 Hz, 1H), 3.54 (d, J = 13.7Hz, 1H), 1.52-1.48 (m, 4H), 0.78 (s, 9H). 445 1H NMR (400 MHz,Methanol-d4) δ 8.43 (s, 1H), 8.13 (s, 1H), 7.62 (d, J = 2.3 Hz, 1H),7.50 (d, J = 7.1 Hz, 1H), 7.48-7.36 (m, 2H), 7.04 (d, J = 2.3 Hz, 1H),6.12 (s, 1H), 5.94 (t, J = 54.6 Hz, 1H), 4.92 (d, J = 14.6 Hz, 1H), 4.56(s, 2H), 4.55 (d, J = 14.7 Hz, 1H), 4.12 (d, J = 13.9 Hz, 1H), 3.69 (d,J = 13.9 Hz, 1H), 1.58-1.50 (m, 4H), 0.96 (s, 9H). 446 1H NMR (400 MHz,Methanol-d4) δ 9.13 (s, 1H), 8.46 (s, 1H), 8.39 (d, J = 7.1 Hz, 1H),8.04 (s, 1H), 7.80 (s, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 6.9Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.98 (t, J = 7.0 Hz, 1H), 6.32 (s,1H), 4.08 (d, J = 13.9 Hz, 1H), 3.89 (ddd, J = 11.5, 7.4, 4.1 Hz, 1H),3.68 (d, J = 13.9 Hz, 1H), 1.25-1.10 (m, 4H), 0.87 (s, 9H). 447 1H NMR(400 MHz, Chloroform-d) δ 8.45 (s, 1H), 7.93 (t, J = 8.1 Hz, 1H), 7.41(s, 1H), 7.35 (d, J = 2.3 Hz, 1H), 6.80 (dd, J = 8.4, 3.2 Hz, 1H), 6.25(s, 1H), 5.93 (s, 1H), 5.91 (t, J = 56.0 Hz, 1H), 5.27 (s, 1H), 3.57 (m,2H), 2.58 (s, 3H), 1.55-1.50 (m, 4H), 0.94 (s, 9H). 448 1H NMR (400 MHz,Methanol-d4) δ 8.47 (s, 1H), 8.13 (s, 1H), 7.74 (s, 1H), 7.69 (d, J =2.3 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.35 (dd, J = 8.6, 7.0 Hz, 1H),7.23 (d, J = 7.0 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.44 (s, 1H), 4.13(d, J = 13.9 Hz, 1H), 3.90-3.79 (m, 1H), 3.69-3.60 (m, 1H), 1.22-1.06(m, 4H), 0.84 (s, 9H). 449 1H NMR (400 MHz, Methanol-d4) δ 9.29 (s, 1H),8.44 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.89 (s, 1H), 7.69 (s, 1H), 7.62(d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.11 (s, 1H), 6.93 (s,1H), 4.04 (d, J = 13.8 Hz, 1H), 3.91-3.77 (m, 1H), 3.73 (d, J = 13.8 Hz,1H), 1.24-1.00 (m, 4H), 0.87 (s, 8H). 450 1H NMR (400 MHz, Methanol-d4)δ 8.94 (dd, J = 4.3, 1.8 Hz, 1H), 8.47 (s, 1H), 8.37 (dd, J = 8.3, 1.8Hz, 1H), 7.93 (dd, J = 8.1, 1.4 Hz, 1H), 7.86 (dd, J = 7.2, 1.3 Hz, 1H),7.76 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.62-7.53 (m, 2H), 7.27 (s, 1H),7.10 (d, J = 2.2 Hz, 1H), 4.02 (d, J = 13.9 Hz, 1H), 3.86-3.70 (m, 2H),1.19-1.04 (m, 4H), 0.80 (s, 9H). 451 1H NMR (400 MHz, Methanol-d4) δ8.28 (s, 2H), 7.74 (d, J = 2.5 Hz, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.44(t, J = 7.5 Hz, 1H), 7.40 (d, J = 7.3 Hz, 1H), 7.21 (d, J = 2.5 Hz, 1H),6.13 (s, 1H), 4.99 (d, J = 14.6 Hz, 1H), 4.59 (d, J = 14.8 Hz, 1H), 4.56(s, 2H), 3.97 (d, J = 13.8 Hz, 1H), 3.55 (d, J = 13.8 Hz, 1H), 1.85-1.74(m, 2H), 1.70-1.61 (m, 2H), 0.93 (s, 9H). 452 1H NMR (400 MHz,Methanol-d4) δ 8.86 (d, J = 15.0 Hz, 2H), 8.01 (d, J = 11.5 Hz, 2H),7.85 (s, 1H), 7.77-7.64 (m, 3H), 7.56 (d, J = 2.5 Hz, 1H), 7.50-7.41 (m,1H), 7.34-7.19 (m, 3H), 7.12 (d, J = 7.4 Hz, 1H), 6.94 (d, J = 2.5 Hz,1H), 6.70 (d, J = 2.5 Hz, 1H), 6.12 (s, 1H), 6.07 (s, 1H), 4.58-4.42 (m,3H), 4.20 (dd, J = 10.0, 5.8 Hz, 1H), 4.02 (dd, J = 11.4, 4.5 Hz, 1H),3.62 (dt, J = 15.5, 7.9 Hz, 2H), 3.20-3.07 (m, 2H), 3.02 (d, J = 11.6Hz, 1H), 2.94 (p, J = 1.7 Hz, 14H), 2.89-2.81 (m, 1H), 2.75 (d, J = 11.6Hz, 1H), 1.66-1.22 (m, 11H), 0.66 (s, 3H), 0.43 (s, 3H), 0.29 (s, 3H),−0.00 (s, 3H). 453 1H NMR (400 MHz, DMSO-d6) δ 9.36 (d, J = 1.3 Hz, 1H),8.42 (s, 2H), 8.04 (dd, J = 8.0, 1.2 Hz, 1H), 7.80 (s, 1H), 7.62 (d, J =7.4 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.29 (s, 1H), 6.49 (d, J = 6.2Hz, 1H), 3.97 (m, 2H), 2.69 (d, J = 1.3 Hz, 3H), 1.71 (d, J = 35.6 Hz,4H), 0.79 (d, J = 1.3 Hz, 9H). 454 1H NMR (400 MHz, Methanol-d4) δ 8.37(s, 1H), 7.92 (s, 1H), 7.84-7.70 (m, 2H), 7.09 (m, 1H), 6.87 (m, 1H),6.19 (s, 1H), 3.96-3.80 (m, 2H), 3.72 (m, 1H), 2.51 (s, 3H), 1.34-0.94(m, 4H), 0.89 (s, 9H). 455 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H),8.35 (m, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.67-7.54 (m, 2H), 7.49 (t, J =7.7 Hz, 1H), 7.35 (d, J = 12.8 Hz, 1H), 6.94 (s, 1H), 6.44 (d, J = 6.1Hz, 1H), 3.89 (dd, J = 13.7, 7.8 Hz, 1H), 3.43 (dd, J = 13.7, 5.4 Hz,1H), 1.72 (m, 2H), 1.64 (m, 2H), 0.77 (s, 9H). 456 1H NMR (400 MHz,DMSO-d6) δ 11.05 (s, 1H), 9.34 (d, J = 1.4 Hz, 1H), 8.07 (s, 1H), 8.01(d, J = 8.2 Hz, 1H), 7.61 (s, 2H), 7.58-7.52 (m, 1H), 7.36 (s, 3H), 7.25(s, 1H), 6.01 (d, J = 13.4 Hz, 1H), 3.94 (s, 1H), 1.13 (s, 13H). 458 1HNMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.48 (s, 1H), 8.05 (dd, J =7.9, 1.4 Hz, 1H), 7.86 (s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.60 (dt, J =15.3, 7.3 Hz, 2H), 7.01 (d, J = 2.3 Hz, 1H), 6.37 (s, 1H), 4.21 (d, J =13.9 Hz, 1H), 3.74 (d, J = 1.8 Hz, 2H), 3.57 (d, J = 13.9 Hz, 1H),1.34-1.25 (m, 2H), 1.21-1.13 (m, 2H), 0.86 (s, 9H). 459 1H NMR (400 MHz,Methanol-d4) δ 9.18 (s, 1H), 8.48 (s, 1H), 7.96 (s, 1H), 7.82 (d, J =8.3 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.42(d, J = 7.6 Hz, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.84 (s, 1H), 4.22 (s,3H), 3.95-3.85 (m, 1H), 3.89 (s, 2H), 1.27-1.10 (m, 4H), 0.84 (s, 9H).460 1H NMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.33 (s, 1H), 8.06(dd, J = 7.6, 1.5 Hz, 1H), 7.90 (s, 1H), 7.88 (d, J = 2.5 Hz, 1H),7.67-7.55 (m, 2H), 7.19 (d, J = 2.5 Hz, 1H), 6.42 (s, 1H), 5.26 (qd, J =8.7, 2.5 Hz, 2H), 3.99 (d, J = 13.7 Hz, 1H), 3.46 (d, J = 13.7 Hz, 1H),0.80 (s, 9H). 461 1H NMR (400 MHz, Methanol-d4) δ 8.99 (s, 1H), 8.77 (m,1H), 8.47 (s, 1H), 8.16-8.05 (m, 2H), 7.87-7.78 (m, 1H), 7.78-7.66 (m,3H), 6.97-6.88 (m, 2H), 4.00 (d, J = 13.9 Hz, 1H), 3.62 (d, J = 13.9 Hz,1H), 1.76-1.58 (m, 4H), 0.70 (s, 9H). 462 1H NMR (400 MHz, Methanol-d4)δ 8.48 m, 3H), 8.23 (m, 1H), 8.11 (m, 1H), 7.96 m, 1H), 7.63 (m, 1H),7.50 (m, 1H), 7.43 (s, 1H), 7.27 m, 1H), 6.45 (s, 1H), 4.08 (d, J = 14.0Hz, 1H), 3.83 (d, J = 14.0 Hz, 1H), 1.31-1.08 (m, 4H), 0.98 (s, 9H). 4631H NMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.49 (s, 1H), 8.06 (dd, J= 8.0, 1.3 Hz, 1H), 7.87 (s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.67-7.54(m, 2H), 7.02 (d, J = 2.3 Hz, 1H), 6.41 (s, 1H), 4.22 (d, J = 13.9 Hz,1H), 3.59 (d, J = 13.9 Hz, 1H), 2.98-2.86 (m, 2H), 2.86-2.73 (m, 2H),2.13-1.96 (m, 2H), 0.86 (s, 9H). 464 1H NMR (400 MHz, Methanol-d4) δ9.22 (s, 1H), 8.59 (d, J = 6.0 Hz, 2H), 8.30 (s, 1H), 8.12 (s, 1H), 8.06(dd, J = 8.1, 1.1 Hz, 1H), 7.85 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 7.4Hz, 1H), 7.61 (dd, J = 8.1, 7.5 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.14(d, J = 6.1 Hz, 2H), 6.45 (s, 1H), 3.94 (d, J = 13.7 Hz, 1H), 3.41 (d, J= 13.7 Hz, 1H), 2.17-1.94 (m, 4H), 0.79 (s, 9H). 465 1H NMR (400 MHz,Methanol-d4) δ 9.21 (s, 1H), 8.34 (s, 1H), 8.08-8.01 (m, 1H), 7.88 (s,1H), 7.87 (d, J = 2.4 Hz, 1H), 7.67-7.62 (m, 1H), 7.62-7.55 (m, 1H),7.18 (d, J = 2.5 Hz, 1H), 6.37 (s, 1H), 4.01 (d, J = 13.7 Hz, 1H), 3.74(d, J = 1.9 Hz, 2H), 3.46 (d, J = 13.8 Hz, 1H), 1.32-1.27 (m, 2H),1.22-1.14 (m, 2H), 0.81 (s, 9H). 466 1H NMR (400 MHz, Methanol-d4) δ9.60 (s, 1H), 9.53 (s, 1H), 8.76 (d, J = 6.1 Hz, 1H), 8.72 (s, 1H), 8.51(s, 1H), 8.01 (d, J = 6.2 Hz, 1H), 7.96 (s, 1H), 7.70 (d, J = 2.3 Hz,1H), 7.01 (d, J = 2.3 Hz, 1H), 6.76 (s, 1H), 4.02 (d, J = 13.9 Hz, 1H),3.96-3.76 (m, 1H), 3.70 (d, J = 13.9 Hz, 1H), 1.24-1.11 (m, 4H), 0.76(s, 9H). 467 1H NMR (400 MHz, Acetonitrile-d3) δ 9.08 (d, J = 4.6 Hz,1H), 8.97 (d, J = 8.6 Hz, 1H), 8.36 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H),7.87 (s, 1H), 7.83-7.70 (m, 2H), 7.65 (s, 1H), 6.90 (d, J = 2.5 Hz, 1H),6.77 (s, 1H), 5.74 (s, 1H), 3.65 (dd, J = 13.3, 6.8 Hz, 1H), 3.48 (dd, J= 13.5, 5.3 Hz, 1H), 1.29 (s, 1H), 1.10 m, 4H), 0.68 (s, 9H). 468 1H NMR(400 MHz, Acetonitrile-d3) δ 8.35 (s, 1H), 8.10 (s, 2H), 7.96 (s, 1H),7.88 (s, 1H), 7.76 (s, 1H), 6.94 (s, 1H), 6.88 (s, 1H), 5.93 (s, 1H),3.84-3.71 (m, 2H), 3.39 (d, J = 13.9 Hz, 1H), 1.21-0.98 (m, 4H), 0.65(s, 9H). 469 1H NMR (400 MHz, Methanol-d4) δ 9.11 (s, 1H), 9.04 (d, J =8.7 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 8.18-8.10 (m, 1H), 7.99-7.90(m, 1H), 7.90-7.82 (m, 2H), 7.80 (s, 1H), 7.14-7.08 (m, 1H), 6.94 (s,1H), 3.79 (d, J = 13.8 Hz, 1H), 3.48 (d, J = 13.8 Hz, 1H), 1.75-1.56 (m,4H), 0.66 (s, 9H). 470 1H NMR (400 MHz, Methanol-d4) δ 8.30 (d, J = 7.5Hz, 2H), 8.19 (d, J = 8.0 Hz, 1H), 8.06 (t, J = 7.7 Hz, 1H), 8.00 (d, J= 7.3 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.15 (s, 1H), 7.00 (s, 1H),3.82 (d, J = 13.7 Hz, 1H), 3.48 (d, J = 13.8 Hz, 1H), 1.82-1.53 (m, 4H),0.68 (s, 9H). 471 1H NMR (400 MHz, Methanol-d4) δ 8.33 (s, 1H), 8.20 (s,1H), 7.84-7.74 (m, 3H), 7.11-7.06 (m, 1H), 6.91-6.84 (m, 1H), 6.25 (s,1H), 3.85 (d, J = 13.8 Hz, 1H), 3.66 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H),1.80-1.65 (m, 4H), 0.88 (s, 9H). 472 1H NMR (400 MHz, Methanol-d4) δ8.30 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.51(d, J = 8.4 Hz, 1H), 7.40-7.31 (m, 1H), 7.26 (d, J = 7.1 Hz, 1H), 7.18(d, J = 2.5 Hz, 1H), 6.50 (s, 1H), 3.88 (d, J = 13.6 Hz, 1H), 3.51 (d, J= 13.7 Hz, 1H), 1.79-1.54 (m, 4H), 0.79 (s, 9H). 473 1H NMR (400 MHz,Methanol-d4) δ 8.36 (s, 1H), 8.05 (s, 1H), 7.84-7.75 (m, 2H), 7.10 (d, J= 2.5 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 6.24 (s, 1H), 5.94 (t, J= 54.7 Hz, 1H), 3.88 (d, J = 13.8 Hz, 1H), 3.68 (d, J = 13.8 Hz, 1H),2.51 (s, 3H), 1.53 (s, 4H), 0.89 (s, 9H). 474 1H NMR (400 MHz,Methanol-d4) δ 8.86 (s, 1H), 7.96 (s, 1H), 7.72 (s, 1H), 7.70 (d, 1H),7.55 (d, J = 2.6 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 7.25 (t, J = 7.7 Hz,1H), 6.69 (d, J = 2.6 Hz, 1H), 6.09 (s, 1H), 3.96 (dd, J = 11.1, 4.9 Hz,1H), 3.68-3.60 (m, 1H), 3.23-3.12 (m, 1H), 3.03 (d, J = 11.5 Hz, 1H),2.96 (p, J = 1.7 Hz, 21H), 2.77 (d, J = 11.5 Hz, 1H), 1.64-1.47 (m, 2H),1.40-1.21 (m, 4H), 0.29 (s, 3H), 0.00 (s, 3H). 475 1H NMR (400 MHz,Methanol-d4) δ 9.24 (s, 1H), 8.36 (s, 1H), 8.21 (s, 1H), 8.10 (d, J =8.3 Hz, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.49(d, J = 7.4 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 6.48 (s, 1H), 4.56-4.47(m, 1H), 3.95 (d, J = 11.4 Hz, 1H), 3.50 (d, J = 11.5 Hz, 2H), 3.22 (d,J = 11.7 Hz, 1H), 1.86-1.77 (m, 2H), 1.76-1.59 (m, 4H), 1.01 (s, 3H),0.78 (s, 3H). 476 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.23 (s,1H), 7.78 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 6.93 (d, J =2.3 Hz, 1H), 6.88 (dd, J = 8.3, 2.8 Hz, 1H), 6.24 (s, 1H), 4.01 (d, J =13.9 Hz, 1H), 3.85 (d, J = 13.9 Hz, 1H), 2.52 (s, 3H), 2.04-1.97 (m,2H), 1.97-1.91 (m, 2H), 0.94 (s, 9H). 477 1H NMR (400 MHz, Methanol-d4)δ 8.51 (s, 1H), 8.05 (s, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.61 (d, J = 2.2Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.7 Hz, 1H), 6.20 (s,1H), 4.11 (d, J = 13.9 Hz, 1H), 3.76 (d, J = 13.9 Hz, 1H), 2.52 (s, 3H),1.89-1.80 (m, 2H), 1.66-1.59 (m, 2H), 0.94 (s, 9H). 478 1H NMR (400 MHz,Methanol-d4) δ 8.52 (s, 1H), 7.95 (s, 1H), 7.81 (t, J = 8.1 Hz, 1H),7.64 (d, J = 2.2 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.6,2.7 Hz, 1H), 6.23 (s, 1H), 4.08 (d, J = 13.9 Hz, 1H), 3.82 (d, J = 13.9Hz, 1H), 3.00-2.90 (m, 1H), 2.90-2.80 (m, 1H), 2.51 (s, 3H), 2.16-1.98(m, 1H), 0.94 (s, 9H). 479 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H),8.22 (s, 1H), 7.80 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.95(d, J = 2.3 Hz, 1H), 6.89 (dd, J = 8.4, 2.8 Hz, 1H), 6.27 (s, 1H), 4.02(d, J = 13.9 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 3.09-2.95 (m, 3H), 2.53(s, 3H), 2.33 (m, 1H), 2.24-2.10 (m, 1H), 0.94 (s, 9H). 480 1H NMR (400MHz, Methanol-d4) δ 8.49 (s, 1H), 7.96 (s, 1H), 7.77 (t, J = 8.1 Hz,1H), 7.62 (d, J = 2.2 Hz, 1H), 6.88 (d, J = 2.3 Hz, 2H), 6.86 (d, J =2.8 Hz, 1H), 6.18 (s, 1H), 4.01 (d, J = 13.9 Hz, 1H), 3.83 (d, J = 13.9Hz, 1H), 2.50 (s, 3H), 1.66 (s, 3H), 1.35-1.29 (m, 2H), 1.09-1.03 (m,2H), 0.93 (s, 9H). 481 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.38(s, 1H), 8.11-7.92 (m, 2H), 7.78 (s, 1H), 7.64 (dd, J = 12.6, 6.8 Hz,2H), 7.55-7.28 (m, 4H), 6.95 (s, 1H), 6.43 (d, J = 5.8 Hz, 1H), 3.97(dd, J = 13.4, 8.5 Hz, 1H), 3.38 (dd, J = 13.7, 5.2 Hz, 1H), 2.90-2.71(m, 2H), 2.73-2.57 (m, 2H), 1.87 (q, J = 8.3 Hz, 2H), 0.78 (s, 9H). 4821H NMR (400 MHz, Acetonitrile-d3) δ 8.45 (s, 1H), 7.85 (t, J = 8.2 Hz,1H), 7.79 (s, 1H), 7.50 (d, J = 2.3 Hz, 1H), 6.87-6.80 (m, 2H), 6.15 (s,1H), 3.90 (dd, J = 13.5, 6.2 Hz, 1H), 3.81 (dd, J = 13.5, 5.6 Hz, 1H),3.72 (s, 2H), 2.52 (s, 3H), 1.29 (s, 1H), 1.19-1.13 (m, 2H), 0.96 (s,9H). 483 1H NMR (400 MHz, Methanol-d4) δ 9.13 (s, 1H), 8.49 (s, 1H),8.25 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.52(t, J = 7.9 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H),6.89 (s, 1H), 4.22 (s, 3H), 3.89 (d, J = 2.5 Hz, 2H), 1.82-1.66 (m, 4H),0.85 (s, 9H). 484 1H NMR (400 MHz, Methanol-d4) δ 9.29 (s, 1H), 8.31 (d,J = 0.6 Hz, 1H), 8.28 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.78 (d, J =2.4 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.20(d, J = 2.5 Hz, 1H), 6.89 (s, 1H), 4.27 (s, 3H), 3.72 (q, J = 13.9 Hz,2H), 1.81-1.65 (m, 4H), 0.81 (s, 9H). 485 1H NMR (400 MHz, Methanol-d4)δ 8.56 (s, 1H), 8.23 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.32 (dd, J =12.3, 2.2 Hz, 1H), 6.95-6.75 (m, 2H), 6.24 (s, 1H), 4.02 (d, J = 13.9Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 2.51 (s, 3H), 2.04-1.88 (m, 4H),0.95 (s, 9H). 486 1H NMR (400 MHz, Methanol-d4) δ 8.54 (s, 1H), 8.05 (s,1H), 7.87 (t, J = 8.1 Hz, 1H), 7.29 (dd, J = 12.5, 2.1 Hz, 1H),6.92-6.82 (m, 1H), 6.78 (d, J = 2.1 Hz, 1H), 6.20 (s, 1H), 4.10 (d, J =13.9 Hz, 1H), 3.76 (d, J = 13.9 Hz, 1H), 2.52 (s, 3H), 1.88-1.77 (m,2H), 1.62 (td, J = 4.2, 1.9 Hz, 2H), 0.94 (s, 9H). 487 1H NMR (400 MHz,DMSO-d6) δ 8.39 (s, 1H), 8.01 (s, 1H), 7.81 (m, 2H), 7.50-7.22 (m, 4H),6.92 (dd, J = 8.5, 3.0 Hz, 1H), 6.82 (d, J = 2.1 Hz, 1H), 6.22 (d, J =6.1 Hz, 1H), 3.94 (dd, J = 13.8, 8.0 Hz, 1H), 3.43 (dd, J = 13.7, 5.1Hz, 1H), 2.88-2.74 (m, 1H), 2.68 (dd, J = 18.4, 8.4 Hz, 2H), 2.46 (s,3H), 1.99-1.76 (m, 2H), 0.81 (s, 9H). 488 1H NMR (400 MHz, DMSO-d6) δ8.35 (s, 1H), 8.06 (s, 1H), 7.77 (t, J = 8.3 Hz, 1H), 7.65 (s, 1H), 7.38(d, J = 7.1 Hz, 1H), 7.25 (d, J = 12.3 Hz, 1H), 6.91 (dd, J = 8.5, 3.0Hz, 1H), 6.83-6.71 (m, 1H), 6.17 (d, J = 6.0 Hz, 1H), 3.95-3.82 (m, 1H),3.45 (dd, J = 13.8, 5.2 Hz, 1H), 2.42 (s, 3H), 1.60 (s, 3H), 1.32-1.18(m, 2H), 1.06-0.94 (m, 2H), 0.80 (s, 9H). 489 1H NMR (400 MHz,Methanol-d4) δ 8.37 (s, 1H), 8.23 (s, 1H), 7.83-7.75 (m, 2H), 7.10 (d, J= 2.6 Hz, 1H), 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.24 (s, 1H), 3.87 (d, J= 13.8 Hz, 1H), 3.71 (d, J = 13.8 Hz, 1H), 2.52 (s, 3H), 2.04-1.96 (m,2H), 1.94 (m, 2H), 0.90 (s, 9H). 490 1H NMR (400 MHz, Methanol-d4) δ8.35 (s, 1H), 8.07 (s, 1H), 7.89 (t, J = 8.1 Hz, 1H), 7.75 (d, J = 2.5Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.85 (m, 1H), 6.20 (s, 1H), 3.94 (d,J = 13.8 Hz, 1H), 3.59 (d, J = 13.8 Hz, 1H), 2.53 (s, 3H), 1.83 (m, 2H),1.62 (m, 2H), 0.89 (s, 9H). 491 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s,1H), 8.23 (s, 1H), 7.86-7.76 (m, 2H), 7.11 (d, J = 2.5 Hz, 1H), 6.88(dd, J = 8.5, 2.8 Hz, 1H), 6.27 (s, 1H), 3.86 (d, J = 13.8 Hz, 1H), 3.72(d, J = 13.8 Hz, 1H), 3.10-2.91 (m, 3H), 2.54 (s, 3H), 2.33 (m, 1H),2.21-2.12 (m, 1H), 0.90 (s, 9H). 492 1H NMR (400 MHz, Methanol-d4) δ8.37 (s, 1H), 7.97 (s, 1H), 7.83-7.74 (m, 2H), 7.08 (d, J = 2.5 Hz, 1H),6.87 (dd, J = 8.6, 2.8 Hz, 1H), 6.19 (s, 1H), 3.87 (d, J = 13.9 Hz, 1H),3.71 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.66 (s, 3H), 1.35-1.28 (m,2H), 1.10-1.01 (m, 2H), 0.89 (s, 9H). 493 1H NMR (400 MHz, Methanol-d4)δ 8.37 (dd, J = 4.5, 1.9 Hz, 1H), 8.21 (s, 1H), 8.20 (s, 1H), 8.17 (dd,J = 9.1, 1.9 Hz, 1H), 7.99 (s, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.14 (dd,J = 9.1, 4.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.45 (s, 1H), 3.77 (d, J= 13.8 Hz, 1H), 3.66 (d, J = 13.8 Hz, 1H), 1.78-1.61 (m, 4H), 0.87 (s,9H). 494 1H NMR (400 MHz, Methanol-d4) δ 8.38 (s, 1H), 7.96 (s, 1H),7.83 (t, J = 8.1 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.10 (s, 1H),6.91-6.81 (m, 1H), 6.23 (s, 1H), 3.93 (d, J = 13.8 Hz, 1H), 3.67 (d, J =13.8 Hz, 1H), 2.94 (m, 2H), 2.90-2.78 (m, 1H), 2.52 (s, 3H), 2.17-1.99(m, 2H), 0.90 (s, 9H). 495 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H),8.22 (s, 1H), 8.14 (s, 1H), 7.80 (t, J = 8.3 Hz, 1H), 7.67 (d, J = 2.1Hz, 1H), 7.57 (s, 1H), 7.07-6.90 (m, 2H), 6.25 (s, 1H), 4.75 (s, 1H),4.62 (s, 1H), 3.99 (dd, J = 13.8, 7.9 Hz, 1H), 3.51 (dd, J = 13.8, 5.3Hz, 1H), 2.45 (s, 3H), 1.42 (dd, J = 8.2, 4.5 Hz, 2H), 1.33 (s, 2H),0.82 (s, 9H).; 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.13 (s, 1H),7.80 (t, J = 8.3 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.47 (s, 1H), 7.36(d, J = 7.4 Hz, 1H), 6.94 (dd, J = 8.5, 3.0 Hz, 1H), 6.91 (s, 1H), 6.23(d, J = 6.7 Hz, 1H), 4.75 (s, 1H), 4.63 (s, 1H), 3.88 (dd, J = 13.8, 8.1Hz, 1H), 3.40 (dd, J = 14.0, 4.8 Hz, 1H), 2.44 (s, 3H), 1.42 (s, 2H),1.33 (s, 2H), 0.79 (d, J = 1.1 Hz, 9H). 496 1H NMR (400 MHz,Methanol-d4) δ 8.47 (s, 1H), 8.09 (d, J = 1.0 Hz, 1H), 7.89 (s, 1H),7.70 (d, J = 2.2 Hz, 1H), 7.56-7.49 (m, 1H), 7.39 (dd, J = 8.5, 7.1 Hz,1H), 7.28 (d, J = 7.1 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.48 (s, 1H),5.91 (t, J = 54.7 Hz, 1H), 4.15 (d, J = 13.9 Hz, 1H), 4.05 (s, 3H), 3.64(d, J = 13.9 Hz, 1H), 1.48 (d, J = 9.0 Hz, 4H), 0.85 (s, 9H). 497 1H NMR(400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.25 (s, 1H), 7.91 (s, 1H), 7.69(d, J = 2.3 Hz, 1H), 7.58-7.51 (m, 1H), 7.25 (dd, J = 8.5, 6.9 Hz, 1H),7.20 (d, J = 6.6 Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.37 (s, 1H), 5.92(t, J = 54.7 Hz, 1H), 4.17 (s, 3H), 4.16 (d, J = 13.8 Hz, 1H), 3.63 (d,J = 13.8 Hz, 1H), 1.52-1.45 (m, 4H), 0.85 (s, 9H). 498 1H NMR (400 MHz,Methanol-d4) δ 8.47 (s, 1H), 7.96 (s, 1H), 7.66 (d, J = 2.2 Hz, 1H),7.64-7.59 (m, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.53-7.48 (m, 1H), 7.34 (d,J = 2.3 Hz, 1H), 7.22 (s, 1H), 5.93 (t, J = 54.8 Hz, 1H), 4.49 (d, J =3.6 Hz, 2H), 4.05 (d, J = 14.0 Hz, 1H), 3.93 (d, J = 14.0 Hz, 1H), 3.20(s, 3H), 1.51 (s, 4H), 1.01 (s, 9H). 499 1H NMR (400 MHz, Methanol-d4) δ9.05 (s, 1H), 8.46 (s, 1H), 8.08 (s, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.65(d, J = 2.3 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H),6.99 (d, J = 2.3 Hz, 1H), 6.86 (s, 1H), 5.93 (t, J = 54.6 Hz, 1H), 4.20(s, 3H), 3.86 (d, J = 1.7 Hz, 2H), 1.54 (s, 4H), 0.84 (s, 9H). 500 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.13 (d, J = 1.0 Hz, 1H),7.88 (s, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.35(dd, J = 8.4, 7.0 Hz, 1H), 7.25 (d, J = 7.0 Hz, 1H), 7.06 (d, J = 2.3Hz, 1H), 6.49 (s, 1H), 5.91 (t, J = 54.7 Hz, 1H), 4.15 (d, J = 13.9 Hz,1H), 3.66 (d, J = 13.8 Hz, 1H), 1.61-1.37 (m, 4H), 0.86 (s, 9H). 501 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.05 (s, 1H), 7.78 (t, J =8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.87(dd, J = 8.4, 2.7 Hz, 1H), 6.23 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 2.50(s, 3H), 1.53 (s, 4H), 0.93 (s, 9H). 502 1H NMR (400 MHz, Methanol-d4) δ8.50 (s, 1H), 8.05 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.25(s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 4.12 (d, J = 14.2 Hz, 1H), 3.90 (d,J = 14.3 Hz, 1H), 2.50 (s, 3H), 2.03-1.90 (m, 1H), 1.76-1.66 (m, 3H),1.54 (s, 4H), 1.19 (s, 3H). 503 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s,1H), 8.14 (s, 1H), 7.87-7.74 (m, 2H), 7.49-7.38 (m, 2H), 7.20 (d, J =2.5 Hz, 1H), 6.93 (dd, J = 8.3, 3.1 Hz, 1H), 6.24 (d, J = 7.2 Hz, 1H),4.74 (s, 1H), 4.62 (s, 1H), 3.85 (dd, J = 13.8, 8.1 Hz, 1H), 3.40 (dd, J= 13.8, 5.1 Hz, 1H), 2.44 (s, 3H), 1.42 (s, 2H), 1.33 (s, 2H), 0.79 (s,9H). 504 1H NMR (400 MHz, Acetonitrile-d3) δ 10.01 (s, 1H), 8.60 (d, J =6.3 Hz, 1H), 8.41 (s, 1H), 8.30 (d, J = 6.3 Hz, 1H), 8.13 (d, J = 7.9Hz, 1H), 8.07-7.96 (m, 2H), 7.83 (s, 1H), 7.58 (d, J = 2.2 Hz, 1H), 6.89(s, 1H), 6.81 (d, J = 2.3 Hz, 1H), 3.95-3.75 (m, 2H), 3.51 (d, J = 13.3Hz, 1H), 1.17-1.07 (m, 4H), 0.69 (s, 9H). 505 1H NMR (400 MHz,Acetonitrile-d3) δ 8.46 (s, 1H), 8.18 (m, 1H), 8.04-7.96 (m, 1H), 7.97(s, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.33-7.22 (m, 2H), 6.96 (d, J = 2.3Hz, 1H), 6.29 (s, 1H), 5.89 (t, J = 54.6 Hz, 1H), 3.98 (dd, J = 13.9,6.3 Hz, 1H), 3.78 (dd, J = 13.8, 5.3 Hz, 1H), 1.52 (d, J = 1.2 Hz, 4H),0.97 (s, 9H). 506 1H NMR (400 MHz, Acetonitrile-d3) δ 8.88 (s, 1H), 8.64(d, J = 5.2 Hz, 1H), 8.42 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.97 (s,1H), 7.70-7.62 (m, 1H), 7.55 (d, J = 2.3 Hz, 1H), 6.98 (d, J = 2.3 Hz,1H), 6.28 (s, 1H), 6.04-5.74 (m, 1H), 3.93 (m, 1H), 3.71 m, 1H), 1.52(s, 4H), 0.96 (s, 9H). 507 1H NMR (400 MHz, Acetonitrile-d3) δ 8.68 (dd,J = 5.8, 1.5 Hz, 1H), 8.46 (s, 1H), 8.41 (dd, J = 8.1, 1.5 Hz, 1H), 7.97(s, 1H), 7.74 (dd, J = 8.1, 5.8 Hz, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.38(s, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.40 (s, 1H), 5.89 (t, J = 54.6 Hz,1H), 3.95-3.79 (m, 2H), 2.79 (s, 3H), 1.53 (d, J = 2.8 Hz, 4H), 0.96 (s,9H). 508 1H NMR (400 MHz, Acetonitrile-d3) δ 9.07 (d, J = 4.8 Hz, 1H),8.94 (d, J = 8.6 Hz, 1H), 8.44 (m, 1H), 8.27-8.20 (m, 1H), 7.92-7.81 (m,3H), 7.76 (m, 1H), 7.56 (m, 1H), 6.85-6.76 (m, 2H), 6.67 (s, 1H), 5.85(t, J = 54.6 Hz, 1H), 3.81 (m, 1H), 3.60 (m, 1H), 1.48 (m, 4H), 0.72 (s,9H). 509 1H NMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 7.93 (t, J = 8.1Hz, 1H), 7.42-7.35 (m, 2H), 6.78 (m, 1H), 6.16 (s, 1H), 5.92 (d, J = 3.1Hz, 1H), 5.90 (t, J = 55.9 Hz, 1H), 5.51 (d, J = 3.1 Hz, 1H), 5.29 (s,2H), 4.99 (s, 1H), 3.55 (m, 2H), 2.57 (s, 3H), 1.53-1.50 (m, 4H), 0.92(s, 9H). 510 1H NMR (400 MHz, Acetonitrile-d3) δ 8.43 (s, 1H), 8.36 (m,1H), 7.94 (s, 1H), 7.97-7.90 (m, 1H), 7.51 (m, 1H), 7.36 (m, 1H), 6.80(m, 1H), 3.82 (m, 1H), 1.52 (s, 4H), 0.98 (s, 9H). 511 1H NMR (400 MHz,DMSO-d6) δ 8.35 (d, J = 1.2 Hz, 1H), 8.19-8.13 (m, 1H), 7.82 (dt, J =15.9, 8.2 Hz, 1H), 7.61 (dd, J = 26.8, 2.1 Hz, 1H), 7.43-7.28 (m, 1H),7.09 (s, 1H), 7.02-6.87 (m, 2H), 6.34 (dd, J = 25.4, 7.3 Hz, 1H),6.29-5.98 (m, 1H), 4.68 (d, J = 18.2 Hz, 1H), 3.92 (s, 1H), 3.78 (d, J =6.9 Hz, 1H), 2.45 (s, 3H), 2.50 (m, 2H), 1.50 (d, J = 4.5 Hz, 4H), 1.22(d, J = 1.2 Hz, 3H), 1.14 (d, J = 1.2 Hz, 3H), 1.09-1.06 (m, 3H), 0.80(s, 3H). 512 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.18 (s, 1H),7.82 (t, J = 8.2 Hz, 1H), 7.63 (dd, J = 2.3, 1.0 Hz, 1H), 7.50-7.34 (m,2H), 7.00-6.90 (m, 2H), 6.29-5.97 (m, 2H), 3.92 (dd, J = 14.0, 7.9 Hz,1H), 3.59 (dd, J = 14.0, 4.9 Hz, 1H), 2.47 (s, 2H), 2.45 (s, 3H), 1.51(s, 4H), 0.90 (d, J = 8.0 Hz, 6H). 513 1H NMR (400 MHz, Methanol-d4) δ8.56 (d, J = 1.9 Hz, 1H), 8.20 (d, J = 1.7 Hz, 1H), 7.79 (t, J = 8.1 Hz,1H), 7.34 (ddd, J = 12.3, 2.3, 1.2 Hz, 1H), 6.95-6.77 (m, 2H), 6.25 (s,1H), 4.04 (dd, J = 13.9, 1.3 Hz, 1H), 3.87 (dd, J = 13.9, 2.1 Hz, 1H),2.50 (s, 3H), 1.83-1.60 (m, 4H), 0.95 (d, J = 1.0 Hz, 9H). 514 1H NMR(400 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.05 (s, 1H), 7.79 (t, J = 8.1Hz, 1H), 7.32 (dd, J = 12.4, 2.2 Hz, 1H), 6.94-6.75 (m, 2H), 6.23 (s,1H), 5.94 (t, J = 54.6 Hz, 1H), 4.02 (d, J = 13.9 Hz, 1H), 3.84 (d, J =13.9 Hz, 1H), 2.50 (s, 3H), 1.54 (s, 4H), 0.94 (s, 9H). 517 1H NMR (400MHz, Methanol-d4) δ 8.50 (s, 1H), 8.03 (s, 1H), 7.80 (t, J = 8.1 Hz,1H), 7.63 (d, J = 2.3 Hz, 1H), 6.89-6.84 (m, 1H), 6.21 (s, 1H), 4.05 (d,J = 14.0 Hz, 1H), 3.81 (d, J = 13.9 Hz, 1H), 2.51 (s, 3H), 1.90 (m, 2H),1.77-1.68 (m, 2H), 0.94 (s, 9H). 518 1H NMR (400 MHz, DMSO-d6) δ8.39-8.30 (m, 2H), 8.26 (d, J = 1.1 Hz, 1H), 8.05 (td, J = 8.3, 2.5 Hz,1H), 7.66-7.57 (m, 2H), 7.47 (s, 1H), 7.20-7.12 (m, 2H), 6.29-5.94 (m,1H), 4.00 (dd, J = 13.9, 8.0 Hz, 1H), 3.45 (dd, J = 13.8, 5.4 Hz, 1H),1.51 (s, 4H), 0.87 (d, J = 1.1 Hz, 9H). 519 1H NMR (400 MHz,Methanol-d4) δ 8.47 (s, 1H), 8.22 (d, J = 5.0 Hz, 1H), 7.78 (s, 1H),7.68 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 3.6 Hz, 1H), 7.23 (d, J = 5.1 Hz,1H), 6.95 (d, J = 2.3 Hz, 1H), 6.60 (d, J = 3.5 Hz, 1H), 6.44 (s, 1H),4.12 (d, J = 13.8 Hz, 1H), 3.86 (s, 3H), 3.60 (d, J = 13.8 Hz, 1H),1.24-1.05 (m, 4H), 0.81 (s, 9H). 520 1H NMR (400 MHz, Methanol-d4) δ8.88 (s, 1H), 8.47 (s, 1H), 8.12 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.68(d, J = 2.2 Hz, 1H), 7.61-7.47 (m, 2H), 7.15 (d, J = 2.3 Hz, 1H), 6.65(s, 1H), 4.15 (d, J = 13.9 Hz, 1H), 4.04 (s, 3H), 3.69 (d, J = 14.0 Hz,1H), 1.79-1.56 (m, 4H), 0.88 (s, 9H). 521 1H NMR (400 MHz, Methanol-d4)δ 8.47 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.70 (d, J = 2.3 Hz, 1H),7.69-7.63 (m, 1H), 7.37 (d, J = 6.9 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H),7.05 (dd, J = 8.4, 6.9 Hz, 1H), 6.64 (s, 1H), 4.22 (s, 3H), 4.15 (d, J =13.9 Hz, 1H), 3.68 (d, J = 13.9 Hz, 1H), 1.76-1.52 (m, 4H), 0.83 (s,9H). 522 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.17 (s, 1H),7.98 (dd, J = 5.3, 4.0 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.39-7.31 (m,2H), 6.97 (d, J = 2.4 Hz, 1H), 6.82 (s, 1H), 4.39 (s, 3H), 3.93 (d, J =13.9 Hz, 1H), 3.78 (d, J = 13.9 Hz, 1H), 1.79-1.63 (m, 4H), 0.78 (s,9H). 523 1H NMR (400 MHz, Methanol-d4) δ 9.25 (s, 1H), 8.31 (s, 1H),8.12 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.57(t, J = 8.0 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H),6.87 (s, 1H), 5.94 (t, J = 54.6 Hz, 1H), 4.26 (s, 3H), 3.71 (d, J = 1.2Hz, 2H), 1.54 (s, 4H), 0.81 (s, 9H). 524 1H NMR (400 MHz, Methanol-d4) δ8.48 (s, 1H), 7.95 (s, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.46 (d, J = 8.3Hz, 1H), 7.28 (dd, J = 8.4, 7.2 Hz, 1H), 6.97 (d, J = 7.1 Hz, 1H), 6.89(d, J = 2.3 Hz, 1H), 6.70 (s, 1H), 3.96 (d, J = 13.8 Hz, 1H), 3.72 (d, J= 13.8 Hz, 1H), 2.52 (s, 3H), 1.84-1.56 (m, 4H), 0.77 (s, 9H). 525 1HNMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 1.4 Hz, 1H), 8.25 (d, J = 1.0 Hz,1H), 8.07 (s, 1H), 7.80 (s, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.59 (s, 1H),7.50 (dt, J = 7.7, 1.2 Hz, 1H), 7.34-7.23 (m, 2H), 7.14 (d, J = 2.2 Hz,1H), 6.46 (s, 1H), 5.19 (s, 1H), 3.98 (s, 3H), 3.40 (dd, J = 13.8, 5.3Hz, 1H), 1.59 (s, 3H), 1.26-1.18 (m, 2H), 1.04-0.96 (m, 2H), 0.81 (s,9H). 526 1H NMR (400 MHz, Methanol-d4) δ 8.33 (s, 1H), 8.24 (s, 1H),8.00 (s, 1H), 7.84 (d, J = 2.5 Hz, 1H), 7.70-7.63 (m, 1H), 7.38 (d, J =6.9 Hz, 1H), 7.24 (d, J = 2.5 Hz, 1H), 7.05 (dd, J = 8.4, 7.0 Hz, 1H),6.62 (s, 1H), 4.22 (s, 3H), 3.94 (d, J = 13.8 Hz, 1H), 3.55 (d, J = 13.7Hz, 1H), 1.72-1.58 (m, 4H), 0.78 (s, 9H). 527 1H NMR (400 MHz,Methanol-d4) δ 8.35 (s, 1H), 8.17 (s, 1H), 7.97 (t, 1H), 7.82 (d, J =2.5 Hz, 1H), 7.36 (d, J = 4.8 Hz, 2H), 7.16 (d, J = 2.6 Hz, 1H), 6.83(s, 1H), 4.41 (s, 3H), 3.76 (d, J = 13.9 Hz, 1H), 3.66 (d, J = 13.8 Hz,1H), 1.78-1.62 (m, 4H), 0.74 (s, 9H). 528 1H NMR (400 MHz, Methanol-d4)δ 8.33 (s, 1H), 7.95 (s, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.45 (d, J = 8.3Hz, 1H), 7.29 (dd, J = 8.4, 7.2 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 7.01(d, J = 7.2 Hz, 1H), 6.70 (s, 1H), 3.76 (d, J = 13.6 Hz, 1H), 3.57 (d, J= 13.5 Hz, 1H), 2.54 (s, 3H), 1.78-1.56 (m, 4H), 0.72 (s, 9H). 529 1HNMR (400 MHz, DMSO-d6) δ 8.30-8.22 (m, 2H), 8.08 (d, J = 0.4 Hz, 1H),7.88 (d, J = 2.3 Hz, 1H), 7.57 (s, 1H), 7.50 (ddd, J = 7.4, 1.9, 1.0 Hz,1H), 7.43-7.34 (m, 2H), 7.34-7.23 (m, 2H), 6.48 (s, 1H), 3.98 (s, 3H),3.91 (dd, J = 13.8, 8.0 Hz, 1H), 3.35 (dd, J = 13.8, 5.2 Hz, 1H), 1.59(s, 3H), 1.27-1.18 (m, 2H), 1.05-0.96 (m, 2H), 0.79 (s, 9H). 530 1H NMR(400 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.95 (s, 1H), 7.78 (t, J = 8.1Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 6.87 (dd, J= 8.4, 2.8 Hz, 1H), 6.20 (s, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.85 (d, J= 13.9 Hz, 1H), 2.49 (s, 3H), 1.64 (s, 9H), 0.93 (s, 9H). 531 1H NMR(400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.98 (s, 1H), 7.77 (t, J = 8.1Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.87 (dd, J= 8.5, 2.8 Hz, 1H), 6.22 (s, 1H), 4.63 (d, J = 47.1 Hz, 2H), 4.03 (d, J= 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.67 (s, 6H),0.93 (s, 9H). 532 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.92 (s,1H), 7.78 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.94 (d, J =2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.27 (tt, J = 56 Hz, J =3.3 Hz, 1H), 6.25 (s, 1H), 4.95-4.86 (m, 2H), 4.04 (d, J = 13.9 Hz, 1H),3.83 (d, J = 14.0 Hz, 1H), 2.50 (s, 3H), 0.94 (s, 9H). 533 1H NMR (400MHz, Acetonitrile-d3) δ 9.88 (s, 1H), 8.51 (s, 1H), 8.22 (m, 1H), 8.12(s, 1H), 8.03-7.92 (m, 1H), 7.87 (m, 3H), 7.46 (m, 1H), 6.95 (s, 1H),6.62 (s, 1H), 6.22 (s, 1H), 3.71 (s, 2H), 3.35 (m, 1H), 1.57-1.45 (m,4H), 0.50 (s, 9H). 534 1H NMR (400 MHz, Acetonitrile-d3) δ 8.43 (s, 1H),8.31 (s, 1H), 7.97 (s, 1H), 7.84 (m, 1H), 7.44 (m, 1H), 6.88-6.75 (m,2H), 6.09 (s, 1H), 3.89 (m, 2H), 3.62-3.51 (m, 2H), 2.51 (s, 3H), 1.73(s, 1H), 1.78-1.65 (m, 1H), 1.65 (s, 2H), 0.98 (s, 9H). 535 1H NMR (400MHz, Acetonitrile-d3) δ 10.37 (s, 1H), 8.56 (d, J = 6.5 Hz, 1H), 8.38(d, J = 6.6 Hz, 1H), 8.18-8.06 (m, 1H), 8.08-7.97 (m, 3H), 7.92 (m, 1H),7.74 (d, J = 2.4 Hz, 1H), 7.53 (s, 1H), 7.09 (d, J = 2.5 Hz, 1H), 6.29(s, 1H), 3.85-3.73 (m, 1H), 3.27 (m, 1H), 1.77-1.60 (m, 3H), 1.56-1.47(m, 1H), 0.42 (s, 9H). 536 1H NMR (400 MHz, Acetonitrile-d3) δ 9.50 (s,1H), 8.83-8.59 (m, 2H), 8.48 (d, J = 6.7 Hz, 1H), 8.31-8.08 (m, 3H),7.87-7.66 (m, 2H), 7.50 (d, J = 2.1 Hz, 1H), 7.26 (s, 1H), 7.08 (d, J =2.3 Hz, 1H), 6.69 (s, 1H), 5.73 (t, J = 54.5 Hz, 1H), 3.95 (dd, J =13.8, 8.1 Hz, 1H), 3.55 (dd, J = 13.8, 5.1 Hz, 1H), 1.48-1.17 (m, 4H),0.50 (s, 9H). 537 1H NMR (400 MHz, Acetonitrile-d3) δ 9.07 (d, J = 4.8Hz, 1H), 8.94 (d, J = 8.6 Hz, 1H), 8.44 (m, 1H), 8.27-8.20 (m, 1H),7.92-7.81 (m, 3H), 7.76 (m, 1H), 7.56 (m, 1H), 6.85-6.76 (m, 2H), 6.67(s, 1H), 5.85 (t, J = 54.6 Hz, 1H), 3.81 (m, 1H), 3.60 (m, 1H), 1.48 (m,4H), 0.72 (s, 9H). 538 1H NMR (400 MHz, Methanol-d4) δ 8.51 (d, J = 7.0Hz, 1H), 8.49 (s, 1H), 8.05 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.68 (d,J = 2.3 Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H),6.86 (t, J = 7.0 Hz, 1H), 6.62 (dd, J = 2.5, 1.0 Hz, 1H), 6.38 (s, 1H),4.09 (d, J = 13.9 Hz, 1H), 3.67 (d, J = 13.9 Hz, 1H), 1.58-1.44 (m, 4H),0.84 (s, 9H). 539 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.03 (s,1H), 7.89 (t, J = 8.1 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 6.89-6.82 (m,1H), 6.75 (d, J = 2.2 Hz, 1H), 6.23 (s, 1H), 5.96 (t, J = 54.7 Hz, 1H),4.59 (dd, J = 11.5, 4.3 Hz, 1H), 4.09-4.01 (m, 1H), 3.58-3.46 (m, 2H),3.21 (d, J = 11.7 Hz, 1H), 2.43 (s, 3H), 2.21-1.99 (m, 1H), 1.94 (d, J =13.1 Hz, 1H), 1.55 (s, 4H), 0.90 (s, 3H), 0.55 (s, 3H). 540 1H NMR (400MHz, Methanol-d4) δ 8.53 (s, 1H), 8.09 (s, 1H), 7.66-7.58 (m, 2H), 7.09(d, J = 2.3 Hz, 1H), 6.94-6.86 (m, 1H), 6.34 (s, 1H), 5.92 (t, J = 54.7Hz, 1H), 4.76 (dd, J = 11.7, 4.4 Hz, 1H), 4.06 (dd, J = 11.8, 4.7 Hz,1H), 3.60-3.49 (m, 2H), 3.25 (d, J = 11.7 Hz, 1H), 2.59 (s, 3H),2.18-2.05 (m, 1H), 1.92 (d, J = 12.6 Hz, 1H), 1.58-1.48 (m, 4H), 1.05(s, 3H), 0.74 (s, 3H). 541 1H NMR (400 MHz, Methanol-d4) δ 8.21 (s, 1H),8.19 (s, 1H), 7.81 (t, J = 8.1 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 6.87(dd, J = 8.5, 2.7 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.22 (s, 1H), 3.81(d, J = 13.7 Hz, 1H), 3.59 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.97-1.90(m, 6H), 0.87 (s, 9H). 542 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H),8.01 (s, 1H), 8.00-7.91 (m, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.45-7.28 (m,2H), 6.95 (d, J = 2.3 Hz, 1H), 6.80 (s, 1H), 5.93 (t, J = 54.6 Hz, 1H),4.38 (s, 3H), 3.95 (d, J = 13.9 Hz, 1H), 3.77 (d, J = 13.9 Hz, 1H),1.61-1.42 (m, 4H), 0.77 (s, 9H). 543 1H NMR (400 MHz, Methanol-d4) δ8.46 (s, 1H), 8.09 (d, J = 1.0 Hz, 1H), 8.01 (s, 1H), 7.70 (d, J = 2.3Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.5, 7.1 Hz, 1H), 7.27(d, J = 7.0 Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.49 (s, 1H), 4.14 (d, J= 13.8 Hz, 1H), 4.05 (s, 3H), 3.64 (d, J = 13.9 Hz, 1H), 1.77-1.55 (m,4H), 0.85 (s, 9H). 544 1H NMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H),8.25 (s, 1H), 8.03 (s, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.55 (d, J = 8.5Hz, 1H), 7.25 (dd, J = 8.6, 6.9 Hz, 1H), 7.19 (d, J = 6.8 Hz, 1H), 7.02(d, J = 2.2 Hz, 1H), 6.37 (s, 1H), 4.17 (s, 3H), 4.14 (d, J = 13.8 Hz,1H), 3.63 (d, J = 13.8 Hz, 1H), 1.74-1.59 (m, 4H), 0.84 (s, 9H). 545 1HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.05 (s, 1H), 7.77 (t, J =8.1 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.88(dd, J = 8.4, 2.7 Hz, 1H), 6.24 (s, 1H), 6.12 (t, J = 56.0 Hz, 1H), 4.03(d, J = 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.76 (s,6H), 0.94 (s, 9H). 546 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H),7.94 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.94(d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.23 (s, 1H),5.10-4.93 (m, 1H), 4.77-4.72 (m, 1H), 4.64-4.60 (m, 1H), 4.05 (d, J =14.0 Hz, 1H), 3.85 (d, J = 14.0 Hz, 1H), 2.50 (s, 3H), 1.57 (d, J = 7.1,3H), 0.94 (s, 9H). 547 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H),8.02 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 6.93(d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.20 (s, 1H), 4.06(d, J = 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.55 (m,1H), 1.27-1.20 (m, 2H), 1.03 (m, 2H), 0.94 (s, 9H), 0.57-0.48 (m, 2H),0.37-0.30 (m, 2H). 548 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H),8.27 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 6.97(d, J = 2.3 Hz, 1H), 6.90 (dd, J = 8.5, 2.8 Hz, 1H), 6.30 (s, 1H),5.28-5.21 (m, 2H), 5.18 (d, J = 8.3 Hz, 2H), 4.03 (d, J = 14.0 Hz, 1H),3.87 (d, J = 14.0 Hz, 1H), 2.52 (s, 3H), 0.94 (s, 9H). 549 1H NMR (400MHz, Acetonitrile-d3) δ 8.44 (s, 1H), 7.82 (t, J = 8.2 Hz, 1H), 7.49 (d,J = 2.3 Hz, 1H), 6.84 (dd, J = 8.4, 3.2 Hz, 1H), 6.78 (s, 1H), 6.17 (s,1H), 3.83 (m, 2H), 1.78-1.65 (m, 2H), 1.65 (m, 2H), 0.95 (s, 9H). 550 1HNMR (400 MHz, Acetonitrile-d3) δ 9.14-9.06 (m, 2H), 8.37 (s, 1H),8.32-8.25 (m, 1H), 8.00-7.81 (m, 4H), 7.74 (d, J = 2.5 Hz, 1H), 6.91 (d,J = 2.5 Hz, 1H), 6.82 (s, 1H), 5.85 (t, J = 54.6 Hz, 1H), 5.80 (s, 1H),3.68 m, 1H), 3.48 (m, 1H), 1.53-1.43 (m, 4H), 0.69 (s, 9H). 551 1H NMR(400 MHz, Acetonitrile-d3) δ 9.65 (m, 1H), 9.12-9.01 (m, 2H), 8.46 (s,1H), 8.42 (m, 1H), 8.31 (s, 1H), 8.06-7.96 (m, 2H), 7.94 (m, 1H), 7.86(s, 1H), 7.64 (m, 1H), 7.50 (s, 1H), 7.23 (m, 1H), 6.88 (s, 1H), 5.83(t, J = 54.6 Hz, 1H), 4.09 (m, 1H), 3.64 (m, 1H), 1.53-1.32 (m, 4H),0.58 (s, 9H). 552 1H NMR (400 MHz, Acetonitrile-d3) δ 9.98 (s, 1H), 8.60(d, J = 6.3 Hz, 1H), 8.38-8.29 (m, 2H), 8.15 (d, J = 8.0 Hz, 1H),8.09-7.98 (m, 3H), 7.76 (d, J = 2.5 Hz, 1H), 6.95-6.88 (m, 2H), 6.30 (s,1H), 5.88 (t, J = 54.6 Hz, 1H), 3.76 (m, 1H), 3.39 (m, 1H), 1.56-1.42(m, 4H), 0.65 (m, 9H). 553 1H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H),8.00 (s, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 6.86(dd, J = 8.5, 2.7 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.19 (s, 1H), 3.82(d, J = 13.7 Hz, 1H), 3.57 (d, J = 13.8 Hz, 1H), 2.93 (s, 6H), 2.51 (s,3H), 1.74-1.62 (m, 4H), 0.88 (s, 9H). 554 1H NMR (400 MHz, Methanol-d4)δ 8.52 (s, 1H), 8.07 (s, 1H), 7.81 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.23(s, 1H), 4.09 (d, J = 13.9 Hz, 1H), 3.81 (d, J = 14.0 Hz, 1H), 3.39 (m,2H), 3.08 (m, 2H), 2.50 (s, 3H), 1.74 (m, 6H), 1.63 (m, 2H), 0.95 (s,9H). 555 1H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H), 8.02 (s, 1H),7.82 (t, J = 8.1 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.5,2.7 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 6.21 (s, 1H), 3.84 (d, J = 13.7Hz, 1H), 3.62-3.52 (m, 5H), 3.40 (m, 4H), 2.53 (s, 3H), 1.77-1.67 (m,2H), 1.65 (m, 2H), 0.89 (s, 9H). 556 1H NMR (400 MHz, Methanol-d4) δ8.50 (s, 1H), 7.81 (s, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.49-7.42 (m, 1H),7.28 (dd, J = 8.4, 7.2 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.90 (d, J =2.3 Hz, 1H), 6.70 (s, 1H), 5.91 (t, J = 54.7 Hz, 1H), 3.99 (d, J = 13.8Hz, 1H), 3.73 (d, J = 13.8 Hz, 1H), 2.52 (s, 3H), 1.50 (s, 4H), 0.77 (s,9H). 557 1H NMR (400 MHz, Methanol-d4) δ 8.32 (s, 1H), 8.11 (d, J = 1.0Hz, 1H), 8.04 (s, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.52 (d, J = 8.4 Hz,1H), 7.39 (dd, J = 8.5, 7.1 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 7.18 (d,J = 2.5 Hz, 1H), 6.49 (s, 1H), 4.05 (s, 3H), 3.94 (d, J = 13.7 Hz, 1H),3.50 (d, J = 13.7 Hz, 1H), 1.76-1.58 (m, 4H), 0.79 (s, 9H). 558 1H NMR(400 MHz, Methanol-d4) δ 8.36 (d, J = 0.6 Hz, 1H), 8.29 (s, 1H), 8.06(s, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.58-7.51 (m, 1H), 7.26 (dd, J = 8.6,6.9 Hz, 1H), 7.23-7.18 (m, 2H), 6.37 (s, 1H), 4.17 (s, 3H), 3.99 (d, J =13.7 Hz, 1H), 3.53 (d, J = 13.7 Hz, 1H), 1.77-1.59 (m, 4H), 0.80 (s,9H). 559 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.02 (s, 1H),7.99-7.94 (m, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.40-7.33 (m, 2H), 7.14 (d,J = 2.5 Hz, 1H), 6.81 (s, 1H), 5.93 (t, J = 54.7 Hz, 1H), 4.40 (s, 3H),3.77 (d, J = 13.9 Hz, 1H), 3.63 (d, J = 13.8 Hz, 1H), 1.55-1.49 (m, 4H),0.72 (s, 9H). 560 1H NMR (400 MHz, Methanol-d4) δ 8.52 (d, J = 7.0 Hz,1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.69 (d, J =2.3 Hz, 1H), 7.28 (dt, J = 7.0, 0.9 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H),6.87 (t, J = 7.0 Hz, 1H), 6.61 (dd, J = 2.4, 0.9 Hz, 1H), 6.39 (s, 1H),4.10 (d, J = 13.9 Hz, 1H), 3.67 (d, J = 13.9 Hz, 1H), 1.79-1.57 (m, 4H),0.83 (s, 9H). 561 1H NMR (400 MHz, Methanol-d4) δ 9.64 (s, 1H), 8.56 (d,J = 6.6 Hz, 1H), 8.48 (s, 1H), 8.41 (d, J = 6.6 Hz, 1H), 8.36 (d, J =8.3 Hz, 1H), 8.18 (d, J = 7.3 Hz, 1H), 8.07 (s, 1H), 7.88 (dd, J = 8.3,7.4 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.87(s, 1H), 4.05 (d, J = 13.9 Hz, 1H), 3.59 (d, J = 13.9 Hz, 1H), 1.88-1.75(m, 2H), 1.64-1.52 (m, 2H), 0.72 (s, 9H). 562 1H NMR (400 MHz,Methanol-d4) δ 9.59 (s, 1H), 8.55 (d, J = 6.5 Hz, 1H), 8.46 (s, 1H),8.38-8.29 (m, 2H), 8.09 (d, J = 7.3 Hz, 1H), 7.96 (s, 1H), 7.85 (t, J =7.8 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.87(s, 1H), 4.00 (d, J = 13.9 Hz, 1H), 3.62 (d, J = 13.9 Hz, 1H), 2.99-2.86(m, 1H), 2.81 (m, 1H), 2.59 (m, 1H), 2.40-2.24 (m, 1H), 2.18-1.95 (m,2H), 0.72 (s, 9H). 563 1H NMR (400 MHz, Methanol-d4) δ 9.59 (s, 1H),8.56 (d, J = 6.5 Hz, 1H), 8.47 (s, 1H), 8.37-8.29 (m, 2H), 8.23 (s, 1H),8.06 (d, J = 7.3 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.67 (d, J = 2.3 Hz,1H), 6.97 (d, J = 2.3 Hz, 1H), 6.89 (s, 1H), 3.98 (d, J = 13.9 Hz, 1H),3.67 (d, J = 13.9 Hz, 1H), 2.01-1.94 (m, 2H), 1.94-1.83 (m, 2H), 0.73(s, 9H). 564 1H NMR (400 MHz, Methanol-d4) δ 9.55 (s, 1H), 8.54 (d, J =6.5 Hz, 1H), 8.45 (s, 1H), 8.28 (m, 2H), 8.03 (d, J = 7.3 Hz, 1H), 7.95(s, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 6.90 (d, J= 2.4 Hz, 1H), 6.82 (s, 1H), 3.97 (d, J = 13.8 Hz, 1H), 3.63 (d, J =13.9 Hz, 1H), 1.63 (s, 3H), 1.29 (m, 2H), 1.08-1.01 (m, 2H), 0.71 (s,9H). 565 1H NMR (400 MHz, Acetonitrile-d3) δ 9.13-8.99 (m, 2H), 8.43 (s,1H), 8.31-8.24 (m, 1H), 7.97-7.87 (m, 2H), 7.86-7.77 (m, 2H), 7.56 (m,1H), 7.01 (s, 1H), 6.91-6.81 (m, 2H), 5.97 (s, 1H), 5.66 (s, 1H), 3.88(m, 1H), 3.60 (m, 1H), 1.94 (m, 1H) 1.73 (m, 1H), 1.56-1.41 (m, 2H),0.73 (s, 9H). 566 1H NMR (400 MHz, Acetonitrile-d3) δ 9.14-9.05 (m, 2H),8.44 (s, 1H), 8.29 (m, 1H), 7.98-7.76 (m, 4H), 7.56 (m, 1H), 7.13 (s,1H), 6.91-6.83 (m, 2H), 6.58 (s, 1H), 5.96 (s, 1H), 3.90 (m, 1H), 3.61(m, 1H), 2.93-2.80 (m, 2H), 2.79-2.64 (m, 2H), 2.12-1.96 (m, 2H), 0.73(s, 9H). 567 1H NMR (400 MHz, Acetonitrile-d3) δ 9.09 (dd, J = 4.8, 1.5Hz, 1H), 8.96 (d, J = 8.5 Hz, 1H), 8.43 (s, 1H), 8.27 (d, J = 8.2 Hz,1H), 7.95-7.83 (m, 3H), 7.80 (dd, J = 8.7, 4.8 Hz, 1H), 7.55 (d, J = 2.3Hz, 1H), 6.93 (s, 1H), 6.87-6.79 (m, 2H), 6.42 (s, 1H), 3.85 (dd, J =13.7, 6.6 Hz, 1H), 3.63 (dd, J = 13.4, 5.1 Hz, 1H), 1.97-1.76 (m, 4H),0.73 (s, 9H). 568 1H NMR (400 MHz, Acetonitrile-d3) δ 9.09 (dd, J = 4.8,1.5 Hz, 1H), 9.01 (d, J = 8.8 Hz, 1H), 8.43 (s, 1H), 8.30-8.22 (m, 1H),7.93-7.86 (m, 2H), 7.90-7.76 (m, 1H), 7.73 (s, 1H), 7.55 (d, J = 2.2 Hz,1H), 6.89 (m, 1H), 6.80 (s, 2H), 3.84 (dd, J = 13.6, 6.7 Hz, 1H), 3.61(dd, J = 13.6, 5.0 Hz, 1H), 1.60 (s, 3H), 1.28-1.19 (m, 2H), 1.05-0.98(m, 2H), 0.72 (s, 9H). 569 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H),8.57 (d, J = 6.0 Hz, 1H), 8.31 (s, 1H), 8.13 (d, J = 5.7 Hz, 3H),7.89-7.83 (m, 2H), 7.69 (t, J = 7.7 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H),7.31-7.19 (m, 2H), 6.90 (d, J = 7.3 Hz, 1H), 4.71 (s, 1H), 4.59 (s, 1H),3.70 (dd, J = 13.7, 7.6 Hz, 1H), 3.42-3.33 (m, 1H), 1.41-1.27 (m, 4H),0.58 (s, 9H). 570 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1H), 8.25 (s,1H), 7.98 (s, 1H), 7.72-7.64 (m, 2H), 7.37 (d, J = 6.9 Hz, 1H),7.11-7.01 (m, 2H), 6.63 (s, 1H), 4.22 (s, 3H), 4.12 (d, J = 13.9 Hz,1H), 3.67 (d, J = 13.9 Hz, 1H), 1.80-1.50 (m, 2H), 1.28 (s, 2H), 0.82(s, 9H). 571 1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.82 (d, J =2.5 Hz, 1H), 7.81 (s, 1H), 7.48-7.41 (m, 1H), 7.29 (dd, J = 8.5, 7.1 Hz,1H), 7.05 (d, J = 2.5 Hz, 1H), 7.00 (d, J = 7.1 Hz, 1H), 6.69 (s, 1H),3.80 (d, J = 13.6 Hz, 1H), 3.58 (d, J = 13.6 Hz, 1H), 2.54 (s, 3H), 1.50(d, J = 2.3 Hz, 4H), 0.72 (s, 9H). 572 1H NMR (400 MHz, Methanol-d4) δ8.51 (d, J = 7.0 Hz, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 7.18 (d, J= 2.5 Hz, 1H), 6.87 (t, J = 7.0 Hz, 1H), 6.63 (dd, J = 2.5, 1.0 Hz, 1H),6.39 (s, 1H), 3.92 (d, J = 13.8 Hz, 1H), 3.53 (d, J = 13.7 Hz, 1H),1.79-1.57 (m, 4H), 0.78 (s, 9H). 573 1H NMR (400 MHz, Methanol-d4) δ8.35 (s, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.85 (d, J = 2.5 Hz, 1H), 7.67(d, J = 8.0 Hz, 1H), 7.38 (d, J = 7.0 Hz, 1H), 7.26 (d, J = 2.5 Hz, 1H),7.05 (dd, J = 8.4, 7.0 Hz, 1H), 6.63 (s, 1H), 4.23 (s, 3H), 3.98 (d, J =13.8 Hz, 1H), 3.57 (d, J = 13.8 Hz, 1H), 1.73-1.58 (m, 4H), 0.79 (s,9H). 574 1H NMR (400 MHz, Acetonitrile-d3) δ 8.41 (s, 1H), 7.81 (t, J =8.2 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.84(dd, J = 8.4, 3.1 Hz, 1H), 6.41 (s, 1H), 6.17 (s, 1H), 3.84-3.69 (m,2H), 2.50 (s, 3H), 1.79-1.61 (m, 4H), 0.94 (s, 9H). 575 1H NMR (400 MHz,Acetonitrile-d3) δ 9.27-9.20 (m, 1H), 9.17-9.10 (m, 1H), 8.40-8.29 (m,2H), 8.05-7.92 (m, 3H), 7.85 (s, 1H), 7.75 (d, J = 2.5 Hz, 1H), 6.93 (d,J = 2.5 Hz, 1H), 6.83 (s, 1H), 5.92 (s, 1H), 5.62 (s, 1H), 3.78-3.68 (m,1H), 3.52-3.42 (m, 1H), 1.76-1.71 (m, 2H), 1.57-1.37 (m, 2H), 0.69 (s,9H). 576 1H NMR (400 MHz, Chloroform-d) δ 8.91 (m, 1H), 8.55 (m, 1H),8.33 (s, 1H), 8.08 (m, 1H), 7.70 (m, 2H), 7.56-7.44 (m, 2H), 7.31 (s,1H), 7.22 (s, 2H), 6.60 (m, 1H), 6.50 (m, 1H), 3.45 (m, 2H), 2.87-2.67(m, 2H), 2.15-1.81 (m, 2H), 0.57 (s, 9H). 577 1H NMR (400 MHz,Acetonitrile-d3) δ 9.14-9.03 (m, 2H), 8.37 (s, 1H), 8.30 (d, J = 8.3 Hz,1H), 8.00-7.84 (m, 4H), 7.73 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 2.5 Hz,1H), 6.82 (s, 1H), 5.82 (s, 1H), 3.68 (dd, J = 13.3, 6.7 Hz, 1H), 3.49(dd, J = 13.4, 5.2 Hz, 1H), 1.97-1.79 (m, 4H), 0.69 (s, 9H). 578 1H NMR(400 MHz, Acetonitrile-d3) δ 9.18-9.08 (m, 2H), 8.33 (d, J = 22.8 Hz,2H), 8.01-7.86 (m, 3H), 7.73 (t, J = 1.2 Hz, 2H), 6.90 (d, J = 2.5 Hz,1H), 6.79 (s, 1H), 6.21 (s, 1H), 5.83 (s, 1H), 3.68 (dd, J = 13.3, 6.8Hz, 1H), 3.48 (dd, J = 13.4, 5.0 Hz, 1H), 1.60 (s, 3H), 1.25 (s, 2H),1.05-0.98 (m, 2H), 0.68 (s, 9H). 579 1H NMR (400 MHz, Methanol-d4) δ8.51 (s, 1H), 7.94 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.22(s, 1H), 5.98-4.79 (m, 1H), 4.00 (d, J = 13.9 Hz, 1H), 3.95-3.81 (m,2H), 2.50 (s, 3H), 2.02-1.89 (m, 1H), 1.67-1.55 (m, 1H), 0.93 (s, 9H).580 1H NMR (400 MHz, Methanol-d4) δ 9.74 (s, 1H), 8.60 (d, J = 6.5 Hz,1H), 8.53 (d, J = 6.8 Hz, 1H), 8.43 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H),8.29 (s, 1H), 8.20 (d, J = 7.4 Hz, 1H), 7.95 (dd, J = 8.3, 7.4 Hz, 1H),7.78 (d, J = 2.5 Hz, 1H), 7.14 (d, J = 2.5 Hz, 1H), 6.91 (s, 1H), 3.79(d, J = 13.8 Hz, 1H), 3.51 (d, J = 13.8 Hz, 1H), 2.05-1.94 (m, 2H),1.94-1.86 (m, 2H), 0.69 (s, 9H). 581 1H NMR (400 MHz, Methanol-d4) δ9.73 (s, 1H), 8.59 (d, J = 6.7 Hz, 1H), 8.53 (d, J = 6.7 Hz, 1H), 8.42(d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 8.19 (d, J = 7.3 Hz, 1H), 8.04 (s,1H), 7.95 (dd, J = 8.3, 7.4 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.10 (d,J = 2.5 Hz, 1H), 6.86 (s, 1H), 3.78 (d, J = 13.8 Hz, 1H), 3.50 (d, J =13.8 Hz, 1H), 1.64 (s, 3H), 1.34-1.25 (m, 2H), 1.09-1.00 (m, 2H), 0.68(s, 9H). 582 1H NMR (400 MHz, DMSO-d6) δ 8.40-8.34 (m, 2H), 7.81 (t, J =8.3 Hz, 1H), 7.68-7.62 (m, 1H), 7.43 (d, J = 7.0 Hz, 1H), 6.90 (dd, J =8.4, 3.1 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 6.30 (dd, J = 21.8, 6.2 Hz,1H), 4.48-4.20 (m, 1H), 2.39 (s, 3H), 1.83-1.59 (m, 4H), 1.26 (dd, J =19.5, 6.6 Hz, 4H), 0.85 (s, 3H), 0.67 (s, 9H) 583 1H NMR (400 MHz,DMSO-d6) δ 8.37 (dd, J = 14.4, 8.7 Hz, 2H), 7.89 (d, J = 2.3 Hz, 1H),7.84-7.76 (m, 1H), 7.52 (d, J = 7.0 Hz, 1H), 7.35-7.29 (m, 1H), 7.05 (d,J = 2.5 Hz, 1H), 6.93-6.83 (m, 2H), 6.70 (d, J = 10.5 Hz, 0H), 6.28 (d,J = 6.5 Hz, 1H), 4.24 (dd, J = 10.5, 6.6 Hz, 1H), 2.39 (s, 3H),1.81-1.60 (m, 4H), 1.26 (dd, J = 17.3, 6.6 Hz, 4H), 0.85 (s, 3H), 0.67(s, 9H). 584 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.33 (s, 1H),7.78 (t, J = 8.1 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 6.99 (d, J = 2.3 Hz,1H), 6.89 (dd, J = 8.5, 2.8 Hz, 1H), 6.31 (s, 1H), 4.38 (ddd, J = 11.7,10.7, 1.5 Hz, 2H), 4.00 (d, J = 14.0 Hz, 1H), 3.91 (d, J = 14.0 Hz, 1H),2.53 (s, 3H), 0.95 (s, 9H). 585 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J =9.9 Hz, 2H), 7.86 (t, J = 8.2 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H),7.49-7.32 (m, 2H), 7.24 (d, J = 8.5 Hz, 1H), 7.01-6.94 (m, 1H), 6.35 (d,J = 7.8 Hz, 1H), 4.17 (s, 1H), 2.06 (s, 1H), 1.89 (d, J = 12.0 Hz, 1H),1.82-1.58 (m, 8H), 1.54-1.12 (m, 6H). 586 1H NMR (400 MHz, Methanol-d4)δ 9.76 (s, 1H), 8.63-8.55 (m, 2H), 8.44 (d, J = 8.2 Hz, 1H), 8.29 (m,2H), 8.13 (s, 1H), 7.96 (dd, J = 8.3, 7.4 Hz, 1H), 7.77 (d, J = 2.5 Hz,1H), 7.10 (d, J = 2.5 Hz, 1H), 6.89 (s, 1H), 3.84 (d, J = 13.8 Hz, 1H),3.44 (d, J = 13.8 Hz, 1H), 1.86-1.77 (m, 2H), 1.63-1.52 (m, 2H), 0.67(s, 9H). 587 1H NMR (400 MHz, Methanol-d4) δ 9.74 (s, 1H), 8.63-8.57 (m,1H), 8.55 (m, 1H), 8.42 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J =7.3 Hz, 1H), 8.03 (s, 1H), 7.95 (dd, J = 8.3, 7.4 Hz, 1H), 7.78 (d, J =2.5 Hz, 1H), 7.13 (d, J = 2.5 Hz, 1H), 6.90 (s, 1H), 3.82 (d, J = 13.8Hz, 1H), 3.48 (d, J = 13.8 Hz, 1H), 2.93 (m, 2H), 2.81 (m, 2H),2.16-1.95 (m, 2H), 0.69 (s, 9H). 588 1H NMR (400 MHz, DMSO-d6) δ 8.37(s, 1H), 8.36 (s, 1H), 7.87 (t, J = 8.3 Hz, 1H), 7.58 (d, J = 2.2 Hz,1H), 7.48-7.37 (m, 2H), 7.08 (d, J = 2.3 Hz, 1H), 6.98 (dd, J = 8.4, 3.0Hz, 1H), 6.34 (d, J = 7.2 Hz, 1H), 4.20 (s, 0H), 2.52 (s, 3H), 2.07 (d,J = 10.4 Hz, 1H), 1.89 (d, J = 12.1 Hz, 1H), 1.84-1.60 (m, 8H),1.54-1.27 (m, 4H), 1.27-1.14 (m, 1H). 589 1H NMR (400 MHz, Methanol-d4)δ 8.38 (s, 1H), 7.95 (s, 1H), 7.84-7.76 (m, 2H), 7.08 (d, J = 2.5 Hz,1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.20 (s, 1H), 3.89 (d, J = 13.9 Hz,1H), 3.71 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.64 (s, 9H), 0.90 (s,9H). 590 1H NMR (400 MHz, Methanol-d4) δ 8.39 (s, 1H), 8.05 (s, 1H),7.83-7.75 (m, 2H), 7.11 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz,1H), 6.24 (s, 1H), 6.12 (t, J = 55.5 Hz, 1H), 3.90 (d, J = 13.8 Hz, 1H),3.72 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.76 (d, J = 1.6 Hz, 6H), 0.90(s, 9H). 591 1H NMR (400 MHz, Methanol-d4) δ 8.39 (s, 1H), 8.21 (s, 1H),7.83-7.75 (m, 2H), 7.11 (d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.4, 2.7 Hz,1H), 6.25 (s, 1H), 3.89 (d, J = 13.9 Hz, 1H), 3.71 (d, J = 13.9 Hz, 1H),2.50 (s, 3H), 1.94 (s, 6H), 0.90 (s, 9H). 592 1H NMR (400 MHz,Methanol-d4) δ 8.48 (s, 1H), 8.05 (s, 1H), 7.76 (m, 1H), 7.60 (d, J =2.2 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.86 (m, 1H), 6.30 (s, 1H), 5.92(t, J = 54.6 Hz, 1H), 3.92 (m, 2H), 2.85 (dt, J = 15.3, 7.5 Hz, 2H),1.53 (s, 4H), 1.15 (t, J = 7.5 Hz, 3H), 0.94 (s, 9H). 593 1H NMR (400MHz, Methanol-d4) δ 8.49 (s, 1H), 8.21 (s, 1H), 7.76 (s, 0H), 7.61 (d, J= 2.3 Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 6.86 (m, 1H), 6.31 (s, 1H),3.93 (m, 2H), 2.94-2.70 (m, 2H), 1.84-1.54 (m, 4H), 1.15 (t, J = 7.5 Hz,3H), 0.94 (s, 9H). 594 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.61(d, J = 6.0 Hz, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 8.03 (d,J = 7.8 Hz, 1H), 7.91-7.79 (m, 2H), 7.67 (d, J = 2.2 Hz, 1H), 7.58 (d, J= 7.3 Hz, 1H), 7.14 (s, 1H), 7.04 (d, J = 6.8 Hz, 1H), 6.95 (s, 1H),4.72 (s, 1H), 4.60 (s, 1H), 3.83-3.70 (m, 1H), 3.26 (dd, J = 13.7, 4.9Hz, 1H), 1.42-1.27 (m, 4H), 0.99 (s, 1H), 0.51 (s, 9H). 595 1H NMR (400MHz, Methanol-d4) δ 8.42 (s, 1H), 8.19 (s, 1H), 7.80 (t, J = 8.1 Hz,1H), 7.06 (d, J = 1.9 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 6.56 (d,J = 1.9 Hz, 1H), 6.26 (s, 1H), 4.04 (m, 4H), 3.83 (d, J = 14.0 Hz, 1H),2.51 (s, 3H), 1.83-1.60 (m, 4H), 0.93 (s, 9H). 596 1H NMR (400 MHz,Methanol-d4) δ 8.42 (s, 1H), 8.22 (s, 1H), 7.80 (t, J = 8.1 Hz, 1H),7.05 (d, J = 1.9 Hz, 1H), 6.95-6.80 (m, 1H), 6.55 (d, J = 1.9 Hz, 1H),6.25 (s, 1H), 4.04 (m, 4H), 3.84 (d, J = 14.0 Hz, 1H), 2.52 (s, 3H),2.08-1.84 (m, 4H), 0.93 (s, 9H). 597 1H NMR (400 MHz, Methanol-d4) δ8.35 (s, 1H), 8.06 (s, 1H), 7.84-7.67 (m, 2H), 7.14 (d, J = 2.5 Hz, 1H),6.86 (m, 1H), 6.30 (s, 1H), 5.93 (t, J = 54.7 Hz, 1H), 3.90-3.68 (m,2H), 2.96-2.76 (m, 2H), 1.58-1.44 (m, 4H), 1.15 (t, J = 7.5 Hz, 3H),0.90 (s, 9H). 598 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.21 (s,1H), 7.85-7.74 (m, 2H), 7.14 (d, J = 2.6 Hz, 1H), 6.86 (m, 1H), 6.31 (s,1H), 3.78 (d, J = 2.6 Hz, 2H), 2.86 (m, 2H), 1.84-1.54 (m, 4H), 1.15 (t,J = 7.5 Hz, 3H), 0.90 (s, 9H). 599 1H NMR (400 MHz, Methanol-d4) δ 8.37(s, 1H), 8.28-8.13 (m, 3H), 7.53 (d, J = 2.3 Hz, 1H), 7.44 (s, 1H), 6.97(d, J = 6.7 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.67 (t, J = 6.9 Hz, 1H),6.29 (s, 1H), 3.81 (d, J = 13.6 Hz, 1H), 3.46 (d, J = 13.6 Hz, 1H),1.78-1.58 (m, 4H), 0.77 (s, 9H). 600 1H NMR (400 MHz, Methanol-d4) δ8.69 (dd, J = 5.6, 1.6 Hz, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 8.34 (dd, J= 8.0, 1.5 Hz, 1H), 7.77 (dd, J = 8.1, 5.6 Hz, 1H), 7.64 (d, J = 2.3 Hz,1H), 7.15 (d, J = 2.3 Hz, 1H), 6.50 (s, 1H), 3.96 (d, J = 1.8 Hz, 2H),3.14 (q, J = 7.6 Hz, 2H), 1.82-1.60 (m, 4H), 1.21 (t, J = 7.6 Hz, 3H),0.97 (s, 9H). 601 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.04 (s,1H), 7.84-7.73 (m, 2H), 7.57-7.35 (m, 3H), 7.25-7.07 (m, 3H), 6.93 (dd,J = 8.4, 3.0 Hz, 1H), 6.25 (d, J = 7.0 Hz, 1H), 5.64 (s, 2H), 3.84 (dd,J = 13.8, 8.0 Hz, 1H), 3.40 (dd, J = 13.8, 5.3 Hz, 1H), 2.44 (s, 3H),0.79 (s, 9H). 602 1H NMR (400 MHz, Methanol-d4) δ 8.70 (dd, J = 5.7, 1.5Hz, 1H), 8.42 (d, J = 8.5 Hz, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 7.82 (dd,J = 8.1, 5.7 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.24 (d, J = 2.5 Hz,1H), 6.48 (s, 1H), 3.77 (s, 2H), 3.17 (q, J = 7.6 Hz, 2H), 1.82-1.64 (m,4H), 1.22 (t, J = 7.6 Hz, 3H), 0.92 (s, 9H). 603 1H NMR (400 MHz,Methanol-d4) δ 8.48 (s, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.75 (dd, J =8.1, 1.1 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H),7.13-7.04 (m, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.84 (s, 1H), 5.92 (t, J =54.6 Hz, 1H), 4.17 (s, 3H), 3.87 (d, J = 2.9 Hz, 2H), 1.52 (s, 4H), 0.80(s, 9H). 604 1H NMR (400 MHz, Methanol-d4) δ 8.63 (dd, J = 5.5, 1.5 Hz,1H), 8.48 (s, 1H), 8.21 (d, J = 5.4 Hz, 2H), 7.66 (dd, J = 8.0, 5.4 Hz,1H), 7.61 (d, J = 2.3 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.44 (s, 1H),5.93 (t, J = 54.4 Hz, 1H), 3.92 (d, J = 2.5 Hz, 2H), 3.09 (q, J = 7.6Hz, 2H), 1.57-1.51 (m, 4H), 1.19 (t, J = 7.6 Hz, 3H), 0.95 (s, 9H). 6051H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.92 (s,1H), 7.82 (d, J = 2.5 Hz, 1H), 7.75 (dd, J = 7.9, 1.0 Hz, 1H), 7.20 (d,J = 7.2 Hz, 1H), 7.17 (d, J = 2.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H),6.84 (s, 1H), 5.92 (t, J = 54.8 Hz, 1H), 4.19 (s, 3H), 3.73 (s, 1H),1.51 (s, 4H), 0.78 (s, 9H). 606 1H NMR (400 MHz, Methanol-d4) δ 8.69(dd, J = 5.7, 1.5 Hz, 1H), 8.47-8.40 (m, 1H), 8.32 (s, 1H), 8.25 (s,1H), 7.82 (dd, J = 8.1, 5.7 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.23 (d,J = 2.5 Hz, 1H), 6.47 (s, 1H), 5.94 (t, J = 54.5 Hz, 1H), 3.84-3.70 (m,2H), 3.16 (q, J = 7.6 Hz, 2H), 1.61-1.51 (m, 4H), 1.22 (t, J = 7.6 Hz,3H), 0.92 (s, 9H). 607 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.34(s, 1H), 8.04 (s, 1H), 7.86-7.79 (m, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.23(d, J = 8.5 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 8.4, 3.1Hz, 1H), 6.29 (d, J = 7.8 Hz, 1H), 2.82 (s, 1H), 2.49 (s, 3H), 2.10 (dt,J = 12.5, 7.7 Hz, 2H), 1.79-1.65 (m, 5H), 1.64-1.54 (m, 1H), 1.50 (d, J= 2.4 Hz, 2H), 1.05 (m, J = 11.7 Hz, 1H). 608 1H NMR (400 MHz, DMSO-d6)δ 8.38 (d, J = 4.0 Hz, 1H), 8.34 (d, J = 0.6 Hz, 1H), 8.07 (s, 1H), 7.84(t, J = 8.3 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.42-7.16 (m, 1H), 7.12(d, J = 2.4 Hz, 1H), 7.01 (dd, J = 8.4, 3.1 Hz, 1H), 6.28 (d, J = 7.9Hz, 1H), 4.11 (t, J = 8.2 Hz, 2H), 3.68 (td, J = 8.7, 2.9 Hz, 2H),2.89-2.82 (m, 1H), 2.48 (s, 3H), 2.03-1.92 (m, 2H), 1.80-1.65 (m, 4H).609 1H NMR (400 MHz, DMSO-d6) δ 8.31-8.22 (m, 2H), 8.01 (s, 1H), 7.87(d, J = 2.4 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.51 (ddd, J = 7.0, 2.4,1.0 Hz, 1H), 7.41-7.32 (m, 2H), 7.33-7.23 (m, 2H), 6.48 (d, J = 6.9 Hz,1H), 3.98 (s, 3H), 3.98-3.86 (m, 2H), 3.34 (dd, J = 13.8, 5.2 Hz, 1H),1.18-1.01 (m, 4H), 0.79 (s, 9H). 610 1H NMR (400 MHz, Methanol-d4) δ8.33 (s, 1H), 7.93 (s, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.75 (d, J = 2.5Hz, 1H), 7.06 (d, J = 2.5 Hz, 1H), 6.94-6.77 (m, 1H), 6.19 (s, 1H), 3.87(d, J = 13.8 Hz, 1H), 3.77 (d, J = 4.5 Hz, 2H), 3.63 (d, J = 13.8 Hz,1H), 2.51 (s, 3H), 1.32 (m, 2H), 1.20 (s, 2H), 0.88 (s, 9H). 611 1H NMR(400 MHz, DMSO-d6) δ 8.45-8.37 (m, 1H), 8.26 (d, J = 10.1 Hz, 1H),8.02-7.83 (m, 2H), 7.64 (t, J = 1.9 Hz, 1H), 7.50-7.41 (m, 1H),7.39-7.32 (m, 1H), 7.31-7.16 (m, 3H), 7.10 (dd, J = 6.8, 2.9 Hz, 1H),7.00 (dd, J = 8.4, 3.0 Hz, 1H), 6.47 (d, J = 7.3 Hz, 1H), 5.02-4.70 (m,1H), 2.56 (d, J = 8.3 Hz, 3H), 1.81-1.65 (m, 5H), 1.39 (dt, J = 8.7, 4.7Hz, 1H), 0.72-0.57 (m, 2H), 0.57-0.29 (m, 2H). 612 1H NMR (400 MHz,DMSO-d6) δ 8.41 (s, 1H), 8.20 (s, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.62(d, J = 2.2 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.18-6.99(m, 6H), 6.89 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 7.1 Hz, 1H), 4.29 (dd, J= 13.9, 8.3 Hz, 1H), 3.64 (dd, J = 13.9, 5.1 Hz, 1H), 2.47 (s, 3H),1.85-1.60 (m, 4H), 1.19 (d, J = 41.4 Hz, 6H). 613 1H NMR (400 MHz,DMSO-d6) δ 8.43-8.38 (m, 1H), 8.27 (d, J = 0.9 Hz, 1H), 7.96-7.79 (m,3H), 7.59-7.52 (m, 2H), 7.48-7.24 (m, 1H), 7.24-7.18 (m, 2H), 7.10 (dd,J = 6.7, 3.0 Hz, 1H), 7.00 (dd, J = 8.4, 3.2 Hz, 1H), 6.47 (d, J = 7.9Hz, 1H), 4.92 (t, J = 8.1 Hz, 1H), 4.75 (t, J = 8.6 Hz, 0H), 2.55 (d, J= 8.7 Hz, 3H), 1.83-1.65 (m, 5H), 1.37 (td, J = 8.6, 8.2, 4.5 Hz, 1H),0.76-0.28 (m, 3H). 614 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.19(s, 1H), 7.88-7.79 (m, 2H), 7.49 (t, J = 7.0 Hz, 2H), 7.19 (d, J = 2.5Hz, 1H), 7.17-6.97 (m, 6H), 6.29 (d, J = 6.6 Hz, 1H), 4.27 (dd, J =14.0, 8.3 Hz, 1H), 3.63 (dd, J = 13.9, 5.1 Hz, 1H), 2.47 (s, 3H),1.83-1.63 (m, 4H), 1.19 (d, J = 42.4 Hz, 6H). 615 1H NMR (400 MHz,DMSO-d6) δ 8.40 (d, J = 2.4 Hz, 2H), 7.99 (t, J = 7.1 Hz, 1H), 7.86 (d,J = 2.3 Hz, 1H), 7.80 (t, J = 8.3 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H),7.34 (d, J = 2.5 Hz, 1H), 6.98 (dd, J = 8.4, 3.0 Hz, 1H), 6.27 (d, J =7.5 Hz, 1H), 4.19 (dd, J = 14.7, 7.6 Hz, 1H), 3.85 (dd, J = 14.7, 6.4Hz, 1H), 2.46 (s, 3H), 1.81-1.63 (m, 4H), 1.29 (d, J = 18.6 Hz, 6H). 6161H NMR (400 MHz, Methanol-d4) δ 9.56 (s, 1H), 8.59 (d, J = 6.2 Hz, 1H),8.48 (s, 1H), 8.14 (s, 1H), 8.04 (d, J = 6.3 Hz, 1H), 7.84 (dd, J = 8.3,5.4 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.44-7.35 (m, 1H), 6.93 (d, J =2.3 Hz, 1H), 6.80 (s, 1H), 3.98 (d, J = 13.9 Hz, 1H), 3.67 (d, J = 14.0Hz, 1H), 1.77-1.55 (m, 3H), 0.73 (s, 10H). 617 1H NMR (400 MHz,Methanol-d4) δ 8.94 (d, J = 4.3 Hz, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.48(s, 1H), 8.10 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.64 (ddd, J = 16.5,8.5, 4.6 Hz, 2H), 6.91 (d, J = 2.4 Hz, 1H), 6.81 (s, 1H), 4.00 (d, J =13.9 Hz, 1H), 3.63 (d, J = 13.9 Hz, 1H), 1.76-1.52 (m, 3H), 0.70 (s,11H). 618 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.38-8.31 (m,1H), 8.06 (s, 1H), 7.73 (dd, J = 8.0, 1.0 Hz, 1H), 7.66 (d, J = 2.3 Hz,1H), 7.53-7.44 (m, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.86 (d, J = 2.3 Hz,1H), 6.82 (d, J = 7.6 Hz, 1H), 6.60 (s, 1H), 4.02 (d, J = 13.8 Hz, 1H),3.66 (d, J = 13.8 Hz, 1H), 3.61 (s, 3H), 1.79-1.59 (m, 4H), 0.78 (s,9H). 619 1H NMR (400 MHz, Methanol-d4) δ 8.87 (s, 1H), 8.54 (s, 1H),8.08 (s, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.42(s, 1H), 5.94 (t, J = 54.6 Hz, 1H), 4.07 (d, J = 13.9 Hz, 1H), 3.91 (d,J = 14.0 Hz, 1H), 2.44 (s, 3H), 1.54 (m, 4H), 1.00 (s, 9H). 620 1H NMR(400 MHz, Methanol-d4) δ 8.79 (s, 1H), 8.49 (s, 1H), 8.00 (s, 1H), 7.69(d, J = 2.3 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 6.31 (s, 1H), 5.91 (t, J= 54.8 Hz, 1H), 4.09 (d, J = 13.9 Hz, 1H), 3.93 (d, J = 14.0 Hz, 1H),2.56 (s, 3H), 1.50 (m, 4H), 1.05 (s, 9H). 621 1H NMR (400 MHz,Methanol-d4) δ 8.35 (s, 1H), 8.01 (s, 1H), 7.80 (t, J = 8.3 Hz, 1H),7.77 (d, J = 2.5 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.4,2.7 Hz, 1H), 6.20 (s, 1H), 3.87 (d, J = 13.8 Hz, 1H), 3.68 (d, J = 13.8Hz, 1H), 2.51 (s, 3H), 1.54 (m, 1H), 1.28-1.19 (m, 2H), 1.09-0.98 (m,2H), 0.89 (s, 9H), 0.58-0.46 (m, 2H), 0.38-0.29 (m, 2H). 622 1H NMR (400MHz, Methanol-d4) δ 8.39 (s, 1H), 7.93 (s, 1H), 7.81-7.74 (m, 2H),7.67-7.60 (m, 1H), 7.56 (dd, J = 7.1, 3.3 Hz, 1H), 7.10 (d, J = 2.6 Hz,1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.22 (s, 1H), 4.98-4.78 (m, 1H),3.92-3.83 (m, 2H), 3.74 (d, J = 13.9 Hz, 1H), 2.51 (s, 3H), 2.01-1.88(m, 1H), 1.60 (m, 1H), 0.90 (s, 9H). 623 1H NMR (400 MHz, Methanol-d4) δ8.39 (s, 1H), 7.94 (s, 1H), 7.82-7.75 (m, 2H), 7.11 (d, J = 2.5 Hz, 1H),6.87 (dd, J = 8.6, 2.8 Hz, 1H), 6.23 (s, 1H), 5.01 (m, 1H), 4.76-4.71(m, 1H), 4.66-4.60 (m, 1H), 3.90 (d, J = 13.9 Hz, 1H), 3.72 (d, J = 13.9Hz, 1H), 2.51 (s, 3H), 1.57 (d, J = 7.1 Hz, 3H), 0.90 (s, 9H). 625 1HNMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 7.98 (s, 1H), 7.83-7.76 (m,2H), 7.08 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.6, 2.7 Hz, 1H), 6.22 (s,1H), 4.62 (d, J = 47.1 Hz, 2H), 3.88 (d, J = 13.8 Hz, 1H), 3.70 (d, J =13.8 Hz, 1H), 2.50 (s, 3H), 1.67 (s, 6H), 0.89 (s, 9H). 626 1H NMR (400MHz, Methanol-d4) δ 9.66 (s, 1H), 8.62 (d, J = 6.4 Hz, 1H), 8.32 (s,1H), 8.24 (d, J = 6.4 Hz, 1H), 8.19 (s, 1H), 7.96 (dd, J = 8.2, 5.2 Hz,1H), 7.80 (d, J = 2.5 Hz, 1H), 7.47 (dd, J = 9.8, 8.3 Hz, 1H), 7.11 (d,J = 2.5 Hz, 1H), 6.83 (s, 1H), 3.78 (d, J = 13.7 Hz, 1H), 3.53 (d, J =13.7 Hz, 1H), 1.79-1.68 (m, 2H), 1.64 (t, J = 9.7 Hz, 2H), 0.69 (s,10H). 627 1H NMR (400 MHz, Methanol-d4) δ 8.95 (dd, J = 4.4, 1.4 Hz,1H), 8.70-8.61 (m, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.81 (d, J = 2.5 Hz,1H), 7.66 (ddd, J = 13.4, 8.4, 4.5 Hz, 2H), 7.48 (dd, J = 10.3, 8.2 Hz,1H), 7.07 (d, J = 2.5 Hz, 1H), 6.82 (s, 1H), 3.78 (d, J = 13.7 Hz, 1H),3.48 (d, J = 13.7 Hz, 1H), 1.78-1.54 (m, 4H), 0.64 (s, 10H). 628 1H NMR(400 MHz, Methanol-d4) δ 9.49 (s, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 8.37(d, J = 8.1 Hz, 1H), 8.26 (s, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.02 (ddd,J = 8.5, 7.0, 1.3 Hz, 1H), 7.90 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 7.68(d, J = 2.3 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.94 (s, 1H), 3.93 (d, J= 13.9 Hz, 1H), 3.68 (d, J = 13.9 Hz, 1H), 1.78-1.58 (m, 4H), 0.73 (s,9H). 629 1H NMR (400 MHz, Methanol-d4) δ 9.36 (d, J = 2.2 Hz, 1H),9.06-9.02 (m, 1H), 8.48 (d, J = 2.1 Hz, 2H), 8.15-8.09 (m, 2H), 7.94(ddd, J = 8.4, 6.9, 1.4 Hz, 2H), 7.77-7.71 (m, 2H), 7.52 (d, J = 2.3 Hz,1H), 7.27 (d, J = 2.3 Hz, 1H), 4.05 (s, 2H), 3.80 (t, J = 6.3 Hz, 2H),3.60 (t, J = 6.3 Hz, 2H), 1.78-1.63 (m, 1H), 1.10 (d, J = 2.1 Hz, 9H).630 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.13 (m, 2H), 7.65 (d,J = 2.3 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 6.36 (s, 1H), 5.93 (t, J =54.6 Hz, 1H), 4.11-3.89 (m, 2H), 2.15 (s, 3H), 1.53 (s, 4H), 1.04 (s,9H). 631 1H NMR (400 MHz, Methanol-d4) δ 8.34 (d, J = 7.9 Hz, 1H), 8.34(s, 1H), 8.08 (s, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.77-7.69 (m, 1H), 7.48(t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H),6.89-6.81 (m, 1H), 6.60 (s, 1H), 3.83 (d, J = 13.6 Hz, 1H), 3.61 (s,3H), 3.54 (d, J = 13.7 Hz, 1H), 1.78-1.59 (m, 4H), 0.73 (s, 9H). 632 1HNMR (400 MHz, Methanol-d4) δ 9.03 (d, J = 6.7 Hz, 1H), 8.46 (s, 1H),8.15 (s, 1H), 8.13-7.98 (m, 3H), 7.65 (d, J = 2.2 Hz, 1H), 7.50 (d, J =6.7 Hz, 1H), 7.12 (s, 1H), 6.77 (s, 1H), 4.09 (s, 3H), 4.06 (d, J = 14.0Hz, 1H), 3.51 (d, J = 14.0 Hz, 1H), 1.84-1.55 (m, 4H), 0.69 (s, 9H). 6331H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 6.9 Hz, 2H), 7.92 (t, J = 7.0Hz, 1H), 7.79 (t, J = 8.3 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 7.36 (d, J= 7.8 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.99-6.92 (m, 1H), 6.24 (d, J =7.0 Hz, 1H), 4.20 (dd, J = 14.7, 7.6 Hz, 1H), 3.81 (dd, J = 14.7, 6.3Hz, 1H), 2.44 (s, 3H), 1.77-1.62 (m, 4H), 1.29 (s, 3H), 1.23 (s, 3H).634 1H NMR (400 MHz, Methanol-d4) δ 8.38 (s, 1H), 7.92 (s, 1H),7.84-7.75 (m, 2H), 7.13 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz,1H), 6.43-6.09 (m, 2H), 4.88 (ddd, J = 14.9, 3.4, 1.1 Hz, 2H), 3.89 (d,J = 13.8 Hz, 1H), 3.70 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H), 0.90 (s, 9H).635 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 3.9 Hz, 2H), 7.80 (t, J =8.3 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H),6.99-6.87 (m, 2H), 6.24 (d, J = 6.5 Hz, 1H), 3.97 (dd, J = 13.9, 8.1 Hz,1H), 3.61 (dd, J = 13.9, 4.8 Hz, 1H), 3.52-3.33 (m, 2H), 2.44 (s, 3H),1.81-1.64 (m, 3H), 0.85 (d, J = 3.2 Hz, 6H). 636 1H NMR (400 MHz,DMSO-d6) δ 8.37 (d, J = 2.2 Hz, 2H), 7.81 (t, J = 8.3 Hz, 1H), 7.61 (d,J = 2.2 Hz, 1H), 7.49-7.35 (m, 2H), 7.02-6.90 (m, 2H), 6.26 (d, J = 7.0Hz, 1H), 5.73 (t, J = 56.1 Hz, 1H), 4.30 (dd, J = 14.6, 7.1 Hz, 1H),3.85 (dd, J = 14.6, 4.9 Hz, 1H), 2.48 (s, 3H), 1.80-1.62 (m, 3H),0.81-0.62 (m, 4H). 637 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 7.2 Hz,2H), 7.86 (d, J = 2.4 Hz, 1H), 7.80 (t, J = 8.2 Hz, 1H), 7.50 (d, J =7.3 Hz, 1H), 7.19 (s, 1H), 6.99-6.90 (m, 1H), 6.25 (d, J = 7.3 Hz, 1H),4.00-3.86 (m, 1H), 3.47 (d, J = 11.0 Hz, 3H), 2.44 (s, 3H), 1.84-1.60(m, 3H), 0.85 (d, J = 3.5 Hz, 6H). 638 1H NMR (400 MHz, DMSO-d6) δ 8.38(s, 2H), 7.87-7.77 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 6.2Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 8.5, 3.0 Hz, 1H), 6.28(d, J = 7.3 Hz, 1H), 5.73 (t, J = 56.1 Hz, 1H), 4.31-4.22 (m, 1H), 3.84(dd, J = 14.6, 4.9 Hz, 1H), 2.48 (s, 3H), 1.83-1.59 (m, 4H), 0.80-0.62(m, 4H). 639 1H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.05 (s, 1H),7.65 (d, J = 2.2 Hz, 1H), 7.22 (s, 1H), 6.11-5.74 (m, 2H), 4.05 (d, J =14.0 Hz, 1H), 3.95 (d, J = 14.1 Hz, 1H), 2.38 (s, 3H), 2.26 (s, 3H),1.52 (s, 4H), 1.04 (s, 9H). 640 1H NMR (400 MHz, Methanol-d4) δ 8.92 (s,1H), 8.41 (s, 1H), 8.11 (s, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.35 (d, J =2.5 Hz, 1H), 6.43 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 3.93 (d, J = 13.9Hz, 1H), 3.77 (d, J = 13.9 Hz, 1H), 2.45 (s, 3H), 1.53 (m, 4H), 0.97 (s,9H). 641 1H NMR (400 MHz, Methanol-d4) δ 8.78 (s, 1H), 8.37 (s, 1H),8.02 (s, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.44 (d, J = 2.5 Hz, 1H), 6.32(s, 1H), 5.92 (t, J = 54.8 Hz, 1H), 3.96 (d, J = 13.9 Hz, 1H), 3.80 (d,J = 13.9 Hz, 1H), 2.56 (s, 3H), 1.50 (m, 4H), 1.02 (s, 9H). 642 1H NMR(400 MHz, Methanol-d4) δ 8.38 (s, 1H), 8.01 (s, 1H), 7.85-7.74 (m, 2H),7.11 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.23 (s, 1H),3.92 (d, J = 13.8 Hz, 1H), 3.68 (d, J = 13.9 Hz, 1H), 2.95 (s, 6H), 2.50(s, 3H), 1.68 (m, 2H), 1.66 (m, 2H), 0.91 (s, 9H). 643 1H NMR (400 MHz,Methanol-d4) δ 8.48 (s, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 2.3Hz, 1H), 6.90-6.83 (m, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.08 (s, 1H), 4.05(d, J = 13.9 Hz, 1H), 3.78-3.68 (m, 2H), 2.43 (s, 3H), 1.33-1.23 (m,4H), 0.90 (s, 9H). 644 1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H),8.26 (s, 1H), 7.85-7.76 (m, 2H), 7.12 (d, J = 2.5 Hz, 1H), 6.89 (dd, J =8.6, 2.7 Hz, 1H), 6.30 (s, 1H), 5.24 (m, 2H), 5.18 (m, 2H), 3.85 (d, J =13.9 Hz, 1H), 3.70 (d, J = 13.8 Hz, 1H), 2.53 (s, 3H), 0.89 (s, 9H). 6451H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.97 (s, 1H), 7.79 (t, J =8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H),6.90-6.85 (m, 1H), 6.22 (s, 1H), 5.08 (q, J = 6.7, 6.1 Hz, 1H), 4.02 (d,J = 13.9 Hz, 1H), 3.82 (d, J = 13.9 Hz, 1H), 3.29-3.16 (m, 4H), 2.51 (s,3H), 0.93 (s, 9H). 646 1H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H),7.91 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.89(d, J = 2.2 Hz, 2H), 6.86 (d, J = 2.8 Hz, 1H), 6.20 (s, 1H), 3.99 (d, J= 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.69 (s, 1H), 2.51 (s, 3H),2.37 (s, 6H), 0.92 (s, 9H). 647 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s,1H), 7.78 (t, J = 8.1 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 6.85 (dd, J =8.6, 2.7 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 6.11 (s, 1H), 4.05 (d, J =13.8 Hz, 1H), 3.72 (d, J = 13.9 Hz, 1H), 3.69-3.58 (m, 1H), 2.42 (s,3H), 2.34 (s, 3H), 1.29-1.15 (m, 4H), 0.90 (s, 9H). 648 1H NMR (400 MHz,Methanol-d4) δ 8.51 (s, 1H), 7.99 (s, 1H), 7.81 (t, J = 8.1 Hz, 1H),7.64 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.5,2.7 Hz, 1H), 6.24 (s, 1H), 5.08 (d, J = 7.1 Hz, 1H), 5.03 (d, J = 7.1Hz, 1H), 4.84-4.82 (m, 12), 4.14 (s, 2H), 4.04 (d, J = 13.9 Hz, 1H),3.83 (d, J = 13.9 Hz, 1H), 2.52 (s, 3H), 0.94 (s, 9H). 649 1H NMR (400MHz, Methanol-d4) δ 8.37 (s, 1H), 7.91 (s, 1H), 7.83-7.72 (m, 2H), 7.08(d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.21 (s, 1H), 3.85(d, J = 13.8 Hz, 1H), 3.72 (d, J = 13.8 Hz, 1H), 2.69 (s, 1H), 2.52 (s,3H), 2.37 (s, 6H), 0.89 (s, 9H). 650 1H NMR (400 MHz, Methanol-d4) δ8.38 (s, 1H), 8.06 (dd, J = 5.4, 1.8 Hz, 1H), 7.92 (s, 1H), 7.81 (dd, J= 7.6, 1.8 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H),7.02 (dd, J = 7.6, 5.4 Hz, 1H), 4.10 (d, J = 14.0 Hz, 1H), 3.78 (ddd, J= 11.4, 7.1, 4.2 Hz, 1H), 3.63 (d, J = 14.0 Hz, 1H), 2.97 (s, 6H),1.12-1.02 (m, 4H), 0.91 (s, 9H). 651 1H NMR (400 MHz, Methanol-d4) δ9.72 (s, 1H), 8.61 (d, J = 6.1 Hz, 1H), 8.50 (s, 1H), 8.18 (s, 1H), 8.09(d, J = 6.1 Hz, 1H), 7.88-7.75 (m, 2H), 7.70 (dd, J = 7.9, 2.3 Hz, 1H),6.91 (d, J = 2.3 Hz, 1H), 6.83 (s, 1H), 4.02 (d, J = 13.9 Hz, 1H), 3.62(d, J = 13.9 Hz, 1H), 1.78-1.54 (m, 4H), 0.70 (s, 9H). 652 1H NMR (400MHz, Methanol-d4) δ 9.56 (s, 1H), 8.59 (d, J = 6.2 Hz, 1H), 8.48 (s,1H), 8.05 (d, J = 6.2 Hz, 1H), 8.01 (s, 1H), 7.84 (dd, J = 8.2, 5.1 Hz,1H), 7.68 (d, J = 2.3 Hz, 1H), 7.39 (dd, J = 9.9, 8.2 Hz, 1H), 6.93 (d,J = 2.3 Hz, 1H), 6.79 (s, 1H), 5.91 (t, J = 54.6 Hz, 1H), 4.00 (d, J =13.9 Hz, 1H), 3.66 (d, J = 13.8 Hz, 1H), 1.50 (d, J = 4.1 Hz, 4H), 0.72(s, 9H). 653 1H NMR (400 MHz, Methanol-d4) δ 8.94 (dd, J = 4.3, 1.4 Hz,1H), 8.60 (dt, J = 8.9, 1.5 Hz, 1H), 8.49 (s, 1H), 7.97 (s, 1H), 7.69(d, J = 2.3 Hz, 1H), 7.64 (ddd, J = 18.1, 8.4, 4.5 Hz, 2H), 7.47 (dd, J= 10.3, 8.2 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 6.80 (s, 1H), 5.90 (t, J= 54.7 Hz, 1H), 4.01 (d, J = 13.9 Hz, 1H), 3.62 (d, J = 13.9 Hz, 1H),1.55-1.42 (m, 4H), 0.70 (s, 9H). 654 1H NMR (400 MHz, DMSO-d6) δ 8.32(s, 1H), 8.03 (s, 1H), 7.78 (t, J = 8.3 Hz, 1H), 7.61-7.40 (m, 2H), 7.34(d, J = 7.4 Hz, 2H), 7.23-7.13 (m, 2H), 6.98-6.89 (m, 1H), 6.24 (d, J =6.8 Hz, 1H), 5.63 (s, 2H), 4.11 (s, 1H), 3.88 (dd, J = 13.8, 8.0 Hz,1H), 3.40 (dd, J = 13.7, 5.2 Hz, 1H), 2.43 (s, 3H), 0.78 (s, 9H). 655 1HNMR (400 MHz, DMSO-d6) δ 8.31-8.21 (m, 2H), 7.99 (s, 1H), 7.62 (d, J =2.1 Hz, 1H), 7.55-7.46 (m, 2H), 7.34-7.23 (m, 3H), 7.22-7.11 (m, 3H),6.49 (d, J = 6.8 Hz, 1H), 5.62 (s, 2H), 4.15 (s, 1H), 4.04-3.93 (m, 4H),3.34 (dd, J = 13.8, 5.1 Hz, 1H), 0.80 (s, 9H). 656 1H NMR (400 MHz,DMSO-d6) δ 8.30-8.20 (m, 2H), 8.00 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H),7.61 (d, J = 7.7 Hz, 1H), 7.56-7.35 (m, 4H), 7.34-7.23 (m, 2H),7.22-7.11 (m, 1H), 6.51 (d, J = 7.0 Hz, 1H), 5.62 (s, 2H), 4.13 (s, 1H),3.98 (s, 3H), 3.99-3.88 (m, 1H), 3.32 (dd, J = 13.8, 5.1 Hz, 1H), 0.79(s, 9H). 657 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.13 (m, 2H),7.78 (d, J = 2.5 Hz, 1H), 7.46 (d, J = 2.5 Hz, 1H), 6.36 (s, 1H), 5.94(t, J = 54.7 Hz, 1H), 3.86 (m, 2H), 2.16 (s, 3H), 1.52 (m, 4H), 1.01 (s,9H). 658 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.22 (d, J = 5.1Hz, 1H), 8.05 (s, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 3.6 Hz,1H), 7.23 (d, J = 5.1 Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 6.59 (d, J =3.6 Hz, 1H), 6.50 (s, 1H), 4.13 (d, J = 13.9 Hz, 1H), 3.86 (s, 3H), 3.60(d, J = 13.9 Hz, 1H), 1.75-1.57 (m, 4H), 0.82 (s, 9H). 659 1H NMR (400MHz, Methanol-d4) δ 9.54 (s, 1H), 8.48 (s, 1H), 8.41 (d, J = 8.3 Hz,2H), 8.18 (s, 1H), 8.05 (d, J = 7.2 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H),7.63 (d, J = 2.2 Hz, 1H), 7.16 (s, 1H), 6.98 (d, J = 2.3 Hz, 1H),5.13-4.50 (m, 21H), 3.93 (d, J = 14.0 Hz, 1H), 3.83 (d, J = 13.9 Hz,1H), 3.01 (s, 3H), 1.79-1.64 (m, 4H), 0.82 (s, 9H). 660 1H NMR (400 MHz,Methanol-d4) δ 8.97 (d, J = 5.4 Hz, 1H), 8.48 (d, J = 8.4 Hz, 2H), 8.28(s, 1H), 8.19 (d, J = 1.2 Hz, 2H), 7.85 (dd, J = 5.4, 1.0 Hz, 1H), 7.73(d, J = 2.3 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.47 (s, 1H), 4.95-4.81(m, 3H), 4.11 (d, J = 14.0 Hz, 1H), 3.72 (d, J = 14.0 Hz, 1H), 2.92 (d,J = 0.9 Hz, 3H), 1.81-1.64 (m, 4H), 0.84 (s, 9H). 661 1H NMR (400 MHz,Methanol-d4) δ 8.39 (s, 1H), 8.34 (s, 1H), 7.84-7.75 (m, 2H), 7.15 (d, J= 2.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.31 (s, 1H), 4.38 (t, J= 10.8, 2H), 3.86 (d, J = 13.9 Hz, 1H), 3.75 (d, J = 13.9 Hz, 1H), 2.54(s, 3H), 0.90 (s, 9H). 662 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H),7.82 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.87 (m, 2H), 6.17(s, 1H), 4.03 (d, J = 13.8 Hz, 1H), 3.79 (d, J = 13.9 Hz, 1H), 3.72 (m,1H), 2.47 (s, 3H), 1.34-1.18 (m, 3H), 0.92 (s, 9H). 663 1H NMR (400 MHz,Methanol-d4) δ 8.48 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3Hz, 1H), 6.94-6.83 (m, 2H), 6.17 (s, 1H), 4.03 (d, J = 13.9 Hz, 1H),3.79 (d, J = 13.9 Hz, 1H), 3.71-3.63 (m, 1H), 2.51 (s, 3H), 1.32-1.17(m, 4H), 0.93 (s, 9H). 664 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H),8.27 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.46(d, J = 3.6 Hz, 1H), 7.34 (d, J = 5.3 Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H),6.70 (d, J = 3.6 Hz, 1H), 6.54 (s, 1H), 3.95 (d, J = 13.8 Hz, 1H), 3.89(s, 3H), 3.47 (d, J = 13.7 Hz, 1H), 1.78-1.52 (m, 4H), 0.77 (s, 9H). 6651H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.08 (s, 1H), 7.65 (d, J =2.3 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 6.29(s, 1H), 6.16 (d, J = 2.0 Hz, 1H), 5.93 (t, J = 54.7 Hz, 1H), 4.08-3.90(m, 2H), 3.85 (s, 3H), 1.54 (s, 4H), 1.02 (s, 9H). 666 1H NMR (400 MHz,Methanol-d4) δ 8.49 (s, 1H), 8.23 (s, 1H), 7.64 (d, J = 2.3 Hz, 1H),7.41 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.31 (s, 1H), 6.15(d, J = 2.0 Hz, 1H), 3.97 (q, J = 14.0 Hz, 2H), 3.85 (s, 3H), 1.84-1.60(m, 4H), 1.01 (s, 9H). 667 1H NMR (400 MHz, Methanol-d4) δ 9.61 (s, 1H),8.44 (d, J = 6.7 Hz, 2H), 8.30 (s, 1H), 8.20 (s, 1H), 8.13 (d, J = 6.5Hz, 1H), 7.96-7.87 (m, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.16 (s, 1H), 7.11(d, J = 2.5 Hz, 1H), 3.74 (d, J = 13.8 Hz, 1H), 3.63 (d, J = 13.8 Hz,1H), 3.04 (s, 3H), 1.74 (s, 2H), 1.66 (s, 2H), 0.76 (s, 9H). 668 1H NMR(400 MHz, Methanol-d4) δ 8.99 (d, J = 5.5 Hz, 1H), 8.53 (s, 1H),8.35-8.15 (m, 4H), 7.90 (d, J = 5.6 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H),7.27 (d, J = 2.5 Hz, 1H), 6.45 (s, 1H), 3.90 (t, J = 13.5 Hz, 1H), 3.52(d, J = 13.9 Hz, 1H), 2.95 (s, 3H), 1.76 (s, 2H), 1.67 (s, 2H), 0.78 (s,9H). 669 1H NMR (400 MHz, Methanol-d4) δ 8.15 (s, 1H), 7.66 (s, 1H),7.55 (t, J = 8.1 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 6.52 (dd, J = 8.5,2.7 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 5.85 (s, 1H), 4.20 (dd, J = 11.6,4.3 Hz, 1H), 3.71 (dd, J = 11.8, 4.7 Hz, 1H), 3.26-3.14 (m, 1H), 3.15(d, J = 11.5 Hz, 1H), 2.86 (d, J = 11.7 Hz, 1H), 2.09 (s, 3H), 1.82-1.66(m, 1H), 1.59 (d, J = 13.2 Hz, 1H), 1.23 (ddd, J = 13.2, 8.2, 5.0 Hz,1H), 1.05-0.79 (m, 2H), 0.79-0.61 (m, 2H), 0.53 (s, 3H), 0.25-0.18 (m,2H), 0.18 (s, 3H), 0.10-−0.05 (m, 2H). 670 1H NMR (400 MHz, Methanol-d4)δ 9.61 (s, 1H), 8.69 (d, J = 6.1 Hz, 1H), 8.33 (s, 1H), 8.23 (s, 1H),8.17 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 6.1 Hz, 1H), 8.02 (d, J = 7.6 Hz,1H), 7.83 (d, J = 2.5 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.91 (s, 1H),3.82 (d, J = 13.8 Hz, 1H), 3.42 (d, J = 13.7 Hz, 1H), 1.79-1.55 (m, 4H),0.62 (s, 9H). 671 1H NMR (400 MHz, Methanol-d4) δ 8.95 (dd, J = 4.3, 1.4Hz, 1H), 8.70-8.63 (m, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.83 (d, J = 2.5Hz, 1H), 7.67 (ddd, J = 15.5, 8.4, 4.6 Hz, 2H), 7.48 (dd, J = 10.3, 8.2Hz, 1H), 7.08 (d, J = 2.5 Hz, 1H), 6.81 (s, 1H), 5.91 (t, J = 54.7 Hz,1H), 3.82 (d, J = 13.7 Hz, 1H), 3.49 (d, J = 13.7 Hz, 1H), 1.55-1.42 (m,4H), 0.65 (s, 9H). 672 1H NMR (400 MHz, Methanol-d4) δ 9.56 (s, 1H),8.59 (d, J = 6.2 Hz, 1H), 8.29 (s, 1H), 8.11 (d, J = 6.2 Hz, 1H), 8.02(s, 1H), 7.87 (dd, J = 8.2, 5.2 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.39(dd, J = 10.0, 8.2 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 6.79 (s, 1H), 5.92(t, J = 54.8 Hz, 1H), 3.76 (d, J = 13.7 Hz, 1H), 3.44 (s, 1H), 1.50 (d,J = 3.2 Hz, 3H), 1.31 (t, J = 7.4 Hz, 1H), 0.65 (s, 9H). 673 1H NMR (400MHz, Methanol-d4) δ 9.64 (s, 1H), 8.58 (s, 1H), 8.49 (d, J = 8.1 Hz,1H), 8.38-8.27 (m, 3H), 8.01 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 2.5 Hz,1H), 7.15 (d, J = 2.5 Hz, 1H), 6.98 (s, 1H), 3.74 (d, J = 13.7 Hz, 1H),3.50 (d, J = 13.9 Hz, 1H), 1.80-1.59 (m, 4H), 0.66 (s, 10H). 674 1H NMR(400 MHz, Methanol-d4) δ 8.39 (s, 1H), 8.06 (s, 1H), 7.80 (d, J = 2.5Hz, 1H), 7.42 (d, J = 2.5 Hz, 1H), 6.14-5.73 (m, 2H), 3.93 (d, J = 13.9Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.37 (s, 3H), 2.26 (s, 3H), 1.51 (m,4H), 1.01 (s, 9H). 675 1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H),7.99 (s, 1H), 7.90 (t, J = 8.1 Hz, 1H), 7.80 (d, J = 2.5 Hz, 1H), 6.90(d, J = 2.5 Hz, 1H), 6.85 (dd, J = 8.4, 2.7 Hz, 1H), 6.19 (s, 1H), 4.35(dd, J = 11.1, 4.9 Hz, 1H), 4.11-3.95 (m, 1H), 3.53 (td, J = 11.6, 3.3Hz, 1H), 3.49-3.42 (m, 1H), 3.18 (d, J = 11.6 Hz, 1H), 2.44 (s, 3H),2.04-1.84 (m, 2H), 1.57 (ddd, J = 13.2, 8.4, 5.0 Hz, 1H), 1.33-1.17 (m,2H), 1.12-0.97 (m, 2H), 0.86 (s, 3H), 0.62-0.51 (m, 2H), 0.49 (s, 3H),0.36 (dt, J = 6.4, 4.8 Hz, 2H). 676 1H NMR (400 MHz, Methanol-d4) δ 8.50(s, 1H), 8.37-8.29 (m, 1H), 8.06 (s, 1H), 7.75 (dd, J = 7.6, 1.3 Hz,1H), 7.68 (d, J = 2.3 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.22 (d, J =7.5 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.61(s, 1H), 4.05 (d, J = 13.8 Hz, 1H), 3.68 (d, J = 13.8 Hz, 1H), 1.79-1.55(m, 4H), 0.80 (s, 9H). 677 1H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H),8.09 (s, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.39 (m, 2H), 6.31 (s, 1H), 6.15(d, J = 2.0 Hz, 1H), 5.94 (t, J = 54.7 Hz, 1H), 3.86 (d, J = 3.9 Hz,4H), 1.53 (s, 4H), 0.98 (s, 9H). 678 1H NMR (400 MHz, Methanol-d4) δ8.35 (s, 1H), 8.22 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.38 (m, 2H), 6.32(s, 1H), 6.14 (d, J = 2.0 Hz, 1H), 3.92-3.73 (m, 5H), 1.81-1.60 (m, 4H),0.97 (s, 9H). 679 1H NMR (400 MHz, Methanol-d4) δ 8.17 (s, 1H), 8.09(dd, J = 2.5, 0.7 Hz, 1H), 7.83 (s, 1H), 7.57 (dd, J = 8.9, 2.5 Hz, 1H),7.47 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.65 (dd, J = 8.9,0.8 Hz, 1H), 3.93-3.81 (m, 1H), 3.04 (s, 6H), 2.03 (s, 1H), 1.21-1.10(m, 4H), 0.91 (s, 9H). 680 1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H),7.85 (t, J = 8.1 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.06 (d, J = 2.5 Hz,1H), 6.91-6.83 (m, 1H), 6.18 (s, 1H), 3.89 (d, J = 13.8 Hz, 1H),3.77-3.68 (m, 1H), 3.63 (d, J = 13.8 Hz, 1H), 2.47 (s, 3H), 1.31-1.21(m, 4H), 0.88 (s, 9H). 681 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H),7.87 (t, J = 8.1 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 2.5 Hz,1H), 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.18 (s, 1H), 3.90 (d, J = 13.8 Hz,1H), 3.66 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H), 1.32-1.15 (m, 4H), 0.90(s, 9H). 682 1H NMR (400 MHz, Methanol-d4) δ 9.01 (dd, J = 4.6, 1.4 Hz,1H), 8.85 (d, J = 8.7 Hz, 1H), 8.48 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H),7.96 (s, 1H), 7.90-7.82 (m, 1H), 7.81-7.73 (m, 2H), 7.69 (d, J = 2.3 Hz,1H), 6.92 (d, J = 2.3 Hz, 1H), 6.86 (s, 1H), 4.03 (d, J = 13.9 Hz, 1H),3.61 (d, J = 13.9 Hz, 1H), 1.56-1.44 (m, 1H), 1.24-1.13 (m, 2H), 0.99(m, 2H), 0.70 (s, 9H), 0.53-0.42 (m, 2H), 0.29 (m, 2H). 683 1H NMR (400MHz, Methanol-d4) δ 8.99 (d, J = 4.4 Hz, 1H), 8.80 (d, J = 8.7 Hz, 1H),8.48 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.99 (s, 1H), 7.88-7.81 (m, 1H),7.78-7.70 (m, 2H), 7.69 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H),6.89 (s, 1H), 6.09 (t, J = 55.6 Hz, 1H), 4.00 (d, J = 13.9 Hz, 1H), 3.64(d, J = 13.9 Hz, 1H), 1.77-1.67 (m, 6H), 0.71 (s, 9H). 684 1H NMR (400MHz, Methanol-d4) δ 9.03 (dd, J = 4.7, 1.5 Hz, 1H), 8.88 (d, J = 8.7 Hz,1H), 8.49 (s, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.88 (dd, J =8.5, 7.3 Hz, 1H), 7.82-7.75 (m, 2H), 7.69 (d, J = 2.3 Hz, 1H), 6.94 (d,J = 2.3 Hz, 1H), 6.89 (s, 1H), 4.60 (d, J = 47.1 Hz, 2H), 4.02 (d, J =13.9 Hz, 1H), 3.64 (d, J = 13.9 Hz, 1H), 1.64 (s, 6H), 0.71 (s, 9H). 6851H NMR (400 MHz, Methanol-d4) δ 9.00 (dd, J = 4.6, 1.4 Hz, 1H), 8.81 (d,J = 8.7 Hz, 1H), 8.48 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.89-7.81 (m,2H), 7.78-7.70 (m, 2H), 7.68 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 2.3 Hz,1H), 6.86 (s, 1H), 4.01 (d, J = 13.9 Hz, 1H), 3.62 (d, J = 13.9 Hz, 1H),2.67 (s, 1H), 2.34 (s, 6H), 0.69 (s, 9H). 686 1H NMR (400 MHz,Methanol-d4) δ 8.51 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 6.94-6.85 (m, 1H), 6.36 (s, 1H),4.00-3.92 (m, 2H), 3.89 (d, J = 14.0 Hz, 1H), 2.54 (s, 3H), 1.47-1.23(m, 4H), 0.94 (s, 9H). 687 1H NMR (400 MHz, Methanol-d4) δ 8.42 (s, 1H),8.37 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.60(d, J = 2.3 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 6.38 (s, 1H), 3.96 (d, J= 14.0 Hz, 1H), 3.81 (d, J = 14.0 Hz, 1H), 2.75 (s, 3H), 2.72 (s, 3H),1.84-1.74 (m, 2H), 1.70 (d, J = 13.9 Hz, 2H), 0.94 (s, 9H). 688 1H NMR(400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.26 (s, 1H), 7.82 (dd, J = 10.0,7.6 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.17 (dd, J = 7.7, 1.5 Hz, 1H),7.07 (d, J = 2.3 Hz, 1H), 6.30 (s, 1H), 4.10 (d, J = 14.0 Hz, 1H), 3.78(d, J = 14.0 Hz, 1H), 2.45 (s, 3H), 1.81-1.71 (m, 2H), 1.72-1.62 (m,2H), 0.96 (s, 9H). 689 1H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H),8.36 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.77-7.66 (m, 2H), 7.20 (d, J =2.5 Hz, 1H), 6.39 (s, 1H), 3.85 (d, J = 13.9 Hz, 1H), 3.69 (d, J = 14.0Hz, 1H), 2.78 (s, 3H), 2.74 (s, 3H), 1.83-1.74 (m, 2H), 1.71 (d, J =14.7 Hz, 2H), 0.92 (s, 9H). 690 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s,1H), 8.27 (s, 1H), 7.87-7.76 (m, 2H), 7.26 (dd, J = 2.5, 0.6 Hz, 1H),7.16 (dd, J = 7.7, 1.5 Hz, 1H), 6.31 (s, 1H), 3.98 (d, J = 13.9 Hz, 1H),3.65 (d, J = 13.9 Hz, 1H), 2.45 (s, 3H), 1.80-1.71 (m, 2H), 1.71-1.62(m, 2H), 0.92 (s, 9H). 691 1H NMR (400 MHz, Methanol-d4) δ 9.37 (s, 1H),8.28 (m, 1H), 8.20 (s, 1H), 8.14-8.05 (m, 2H), 7.87-7.75 (m, 2H), 7.60(m, 1H), 7.40 (m, 1H), 6.69 (m, 1H), 6.58 (s, 1H), 3.73 (m, 1H), 3.36(m, 1H), 3.07 (s, 1H), 2.93 (s, 1H), 1.23 (m, 1H), 0.90 (m, 2H),0.74-0.67 (m, 2H), 0.44 (s, 9H), 0.20 (m, 2H), 0.02 (m, 2H). 692 1H NMR(400 MHz, Methanol-d4) δ 9.59 (s, 1H), 8.56 (m, 1H), 8.48 (s, 1H), 8.32(m, 2H), 8.05 (d, J = 7.3 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.85 (t, J= 7.8 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 6.97 (m, 1H), 6.88 (s, 1H),3.98 (m, 1H), 3.94-3.76 (m, 1H), 3.68 (m, 1H), 2.01-1.88 (m, 1H), 1.61(m, 1H), 0.74 (s, 9H). 693 1H NMR (400 MHz, Methanol-d4) δ 9.54 (s, 1H),8.54 (m, 1H), 8.46 (m, 1H), 8.28 (m, 2H), 8.08-7.98 (m, 2H), 7.86-7.78(m, 1H), 7.67 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.88 (s,1H), 6.10 (t, J = 55.6 Hz, 1H), 4.04-3.92 (m, 2H), 3.64 (m, 1H), 1.73(s, 6H), 0.71 (s, 9H). 694 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H),8.27 M, 1H), 8.00 (M, 2H), 7.80 (s, 0H), 7.68 (s, 1H), 6.89 (M, 2H),4.98-4.78 (m, 26H), 4.73-4.63 (m, 2H), 4.57 (s, 1H), 3.96 (d, J = 13.7Hz, 1H), 3.62 (d, J = 13.7 Hz, 1H), 1.67 (s, 6H), 0.71 (s, 9H). 695 1HNMR (400 MHz, Methanol-d4) δ 9.63 (s, 1H), 8.58 (d, J = 6.5 Hz, 1H),8.49 (s, 1H), 8.36 (d, J = 6.7 Hz, 2H), 8.09 (m, 1H), 7.96 (s, 1H),7.92-7.83 (m, 1H), 7.68 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H),6.88 (s, 1H), 4.06-3.96 (m, 1H), 3.67 (m, 1H), 3.36 (s, 1H), 2.70 (s,1H), 2.36 (s, 6H), 1.12 (s, 1H), 0.73 (s, 9H). 696 1H NMR (400 MHz,Methanol-d4) δ 9.66 (s, 1H), 8.57 (d, J = 6.7 Hz, 1H), 8.45 (d, J = 6.7Hz, 1H), 8.36 (m, 1H), 8.28 (s, 1H), 8.14 (m, 1H), 8.07 (s, 1H), 7.90(m, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H), 6.86 (s,1H), 3.78 (d, J = 13.8 Hz, 1H), 3.48 (d, J = 13.8 Hz, 1H), 1.20 (s, 2H),1.00 (s, 2H), 0.67 (s, 9H), 0.53-0.46 (m, 2H), 0.30 (d, J = 5.2 Hz, 2H).697 1H NMR (400 MHz, Methanol-d4) δ 9.66 (s, 1H), 8.57 (d, J = 6.6 Hz,1H), 8.45 (d, J = 6.6 Hz, 1H), 8.37 (m, 1H), 8.28 (s, 1H), 8.13 (m, 1H),7.99-7.86 (m, 2H), 7.77 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H),6.87 (s, 1H), 3.76 (d, J = 13.7 Hz, 1H), 3.49 (d, J = 13.7 Hz, 1H), 2.68(s, 1H), 2.35 (s, 6H), 0.66 (s, 9H). 698 1H NMR (400 MHz, Methanol-d4) δ8.90 (dd, J = 4.6, 1.6 Hz, 1H), 8.53 (d, J = 8.3 Hz, 1H), 8.45 (s, 1H),8.16 (s, 1H), 8.15-8.13 (m, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.81-7.76 (m,1H), 7.74 (d, J = 2.3 Hz, 1H), 7.65 (dd, J = 8.3, 4.5 Hz, 1H), 7.07 (d,J = 2.3 Hz, 1H), 6.38 (s, 1H), 4.10 (d, J = 14.0 Hz, 1H), 3.63 (d, J =14.0 Hz, 1H), 1.78-1.69 (m, 2H), 1.66 (s, 2H), 0.77 (s, 9H). 699 1H NMR(400 MHz, Methanol-d4) δ 8.92 (dd, J = 4.7, 1.6 Hz, 1H), 8.61-8.56 (m,1H), 8.46 (s, 1H), 8.15 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 8.03 (s, 1H),7.81 (dd, J = 8.5, 1.7 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.69 (dd, J =8.4, 4.6 Hz, 1H), 7.08 (d, J = 2.3 Hz, 1H), 6.38 (s, 1H), 5.94 (t, J =54.7 Hz, 1H), 4.11 (d, J = 14.0 Hz, 1H), 3.64 (d, J = 14.0 Hz, 1H), 1.52(d, J = 2.4 Hz, 4H), 0.78 (s, 9H). 700 1H NMR (400 MHz, Methanol-d4) δ8.32 (d, J = 7.6 Hz, 1H), 8.32 (s, 1H), 8.07 (s, 1H), 7.80 (d, J = 2.5Hz, 1H), 7.76 (dd, J = 7.6, 1.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.22(d, J = 7.5 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H),6.61 (s, 1H), 3.81 (d, J = 13.6 Hz, 1H), 3.53 (d, J = 13.6 Hz, 1H),1.80-1.54 (m, 4H), 0.74 (s, 9H). 701 1H NMR (400 MHz, Methanol-d4) δ8.86 (s, 1H), 8.51 (s, 1H), 8.24 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.14(d, J = 2.4 Hz, 1H), 6.42 (s, 1H), 4.05 (d, J = 14.0 Hz, 1H), 3.87 (d, J= 13.9 Hz, 1H), 2.44 (s, 3H), 1.87-1.57 (m, 4H), 0.99 (s, 9H). 702 1HNMR (400 MHz, Methanol-d4) δ 8.85 (s, 1H), 8.50 (s, 1H), 8.06 (s, 1H),7.61 (d, J = 2.3 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.37 (s, 1H), 4.03(d, J = 14.0 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 2.44 (s, 3H), 1.61-1.47(m, 1H), 1.23 (d, J = 2.7 Hz, 2H), 0.99 (m, 11H), 0.53 (dd, J = 8.1, 1.8Hz, 2H), 0.40-0.27 (m, 2H). 703 1H NMR (400 MHz, Methanol-d4) δ9.11-9.02 (m, 2H), 8.30 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.04 (s, 1H),8.00-7.92 (m, 1H), 7.87 (m, 2H), 7.80 (d, J = 2.5 Hz, 1H), 7.08 (d, J =2.5 Hz, 1H), 6.88 (s, 1H), 3.80 (d, J = 13.7 Hz, 1H), 3.46 (d, J = 13.8Hz, 1H), 1.51 (m, 1H), 1.20 (m, 2H), 1.05-0.93 (m, 2H), 0.65 (s, 9H),0.56-0.43 (m, 2H), 0.30 (m, 2H). 704 1H NMR (400 MHz, Methanol-d4) δ9.07 (d, J = 4.8 Hz, 1H), 9.01 (d, J = 8.7 Hz, 1H), 8.30 (s, 1H), 8.12(d, J = 8.5 Hz, 1H), 8.00-7.90 (m, 2H), 7.90-7.82 (m, 2H), 7.79 (d, J =2.5 Hz, 1H), 7.10 (d, J = 2.7 Hz, 1H), 6.90 (s, 1H), 4.95-4.79 (m, 1H),3.86 (m, 1H), 3.78 (d, J = 13.7 Hz, 1H), 3.54-3.45 (m, 1H), 2.05-1.84(m, 1H), 1.68-1.51 (m, 1H), 0.66 (m, 9H) 705 1H NMR (400 MHz,Methanol-d4) δ 9.06 (d, J = 4.7 Hz, 1H), 8.99 (d, J = 8.6 Hz, 1H), 8.29(s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.06 (s, 1H), 7.98-7.87 (m, 1H),7.87-7.73 (m, 3H), 7.09 (d, J = 2.6 Hz, 1H), 6.91 (s, 1H), 6.09 (t, J =55.5 Hz, 1H), 3.78 (d, J = 13.8 Hz, 1H), 3.47 (d, J = 13.8 Hz, 1H), 1.73(s, 6H), 0.65 (s, 9H). 706 1H NMR (400 MHz, Methanol-d4) δ 9.07 (d, J =4.7 Hz, 1H), 9.03 (d, J = 8.9 Hz, 1H), 8.30 (s, 1H), 8.12 (d, J = 8.5Hz, 1H), 7.98-7.91 (m, 2H), 7.84 (m, 2H), 7.79 (d, J = 2.5 Hz, 1H), 7.08(d, J = 2.5 Hz, 1H), 6.89 (s, 1H), 3.78 (d, J = 13.8 Hz, 1H), 3.46 (d, J= 13.7 Hz, 1H), 2.67 (s, 1H), 2.35 (s, 6H), 0.64 (s, 9H). 707 1H NMR(400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.83 (t, J = 8.1 Hz, 1H), 7.65(d, J = 2.3 Hz, 1H), 6.90-6.81 (m, 2H), 6.14-5.81 (m, 2H), 4.12 (d, J =13.9 Hz, 1H), 3.69 (d, J = 13.9 Hz, 1H), 2.41 (s, 3H), 1.70 (m, 2H),1.62 (m, 2H), 0.90 (s, 9H). 708 1H NMR (400 MHz, Methanol-d4) δ 9.02(dd, J = 5.0, 1.6 Hz, 1H), 8.84 (d, J = 8.3 Hz, 1H), 8.29 (s, 1H), 8.22(s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.93 (dd, J = 8.7, 1.7 Hz, 1H),7.89-7.81 (m, 2H), 7.22 (d, J = 2.5 Hz, 1H), 6.41 (s, 1H), 5.95 (t, J =54.6 Hz, 1H), 3.91 (d, J = 13.9 Hz, 1H), 3.47 (d, J = 13.9 Hz, 1H), 1.54(s, 4H), 0.72 (s, 9H). 709 1H NMR (400 MHz, Methanol-d4) δ 8.99 (dd, J =4.3, 1.5 Hz, 1H), 8.60 (dd, J = 8.7, 1.5 Hz, 1H), 8.50 (s, 1H), 8.12 (s,1H), 7.87 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.66 (dd, J =8.7, 4.3 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H),6.83 (s, 1H), 4.03 (d, J = 13.8 Hz, 1H), 3.58 (d, J = 13.9 Hz, 1H),1.76-1.55 (m, 4H), 0.67 (s, 9H). 710 1H NMR (400 MHz, Methanol-d4) δ9.05 (dd, J = 4.2, 1.5 Hz, 1H), 8.67 (dd, J = 8.8, 1.6 Hz, 1H), 8.31 (s,1H), 8.21 (d, J = 7.5 Hz, 2H), 7.84-7.79 (m, 2H), 7.69 (dd, J = 8.7, 4.2Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.92 (s, 1H), 3.81 (d, J = 13.7 Hz,1H), 3.37 (d, J = 13.7 Hz, 1H), 1.77-1.55 (m, 4H), 0.58 (s, 10H). 711 1HNMR (400 MHz, Methanol-d4) δ 8.48 (d, J = 3.3 Hz, 1H), 8.35 (d, J = 7.9Hz, 1H), 7.75 (t, J = 4.3 Hz, 2H), 7.65 (d, J = 3.3 Hz, 1H), 7.54-7.45(m, 1H), 7.40 (m, 1H), 6.83 (m, 2H), 6.56 (d, J = 3.2 Hz, 1H), 4.01 (m,1H), 3.75-3.66 (m, 1H), 2.69 (d, J = 3.3 Hz, 1H), 2.36 (d, J = 3.3 Hz,6H), 0.80 (s, 9H). 712 1H NMR (400 MHz, Methanol-d4) δ 9.17 (s, 1H),8.26 (s, 1H), 8.14 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 8.09 (s, 1H), 7.88(d, J = 7.2 Hz, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.68-7.62 (m, 1H), 7.02(d, J = 2.5 Hz, 1H), 6.78 (s, 1H), 3.73 (d, J = 13.6 Hz, 1H), 3.54-3.44(m, 3H), 1.76-1.58 (m, 3H), 0.64 (s, 9H). 713 1H NMR (400 MHz,Methanol-d4) δ 8.48 (d, J = 1.1 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.78(s, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.48 (t, J= 7.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 7.3 Hz, 2H), 6.56(s, 1H), 4.04 (d, J = 13.8 Hz, 1H), 3.64 (d, J = 13.8 Hz, 1H), 3.61 (s,3H), 2.67 (s, 1H), 2.35 (s, 6H), 0.76 (s, 9H). 714 1H NMR (400 MHz,Acetonitrile-d3) δ 8.40 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.82-7.75 (m,2H), 7.53 (d, J = 2.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.31 (d, J =7.7 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.60 (s, 1H), 6.48 (s, 1H), 6.24(s, 2H), 3.77-3.56 (m, 5H), 3.54 (s, 3H), 3.04 (m, 2H), 2.35 (s, 2H),1.42 (s, 9H), 0.80 (s, 9H). 715 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s,1H), 7.93 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.60 (d, J = 2.3 Hz, 1H),6.86 (dd, J = 8.5, 2.8 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 6.17 (s, 1H),4.30 (d, J = 15.0 Hz, 1H), 4.14 (d, J = 15.0 Hz, 1H), 2.49 (s, 3H), 1.64(s, 9H), 1.12 (d, J = 2.2 Hz, 6H). 716 1H NMR (400 MHz, Methanol-d4) δ8.51 (d, J = 0.7 Hz, 1H), 7.91 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.63(d, J = 2.3 Hz, 1H), 6.94-6.84 (m, 2H), 6.18 (s, 1H), 4.02 (d, J = 13.9Hz, 1H), 3.94-3.79 (m, 2H), 2.50 (s, 3H), 1.27-1.10 (m, 4H), 0.93 (s,9H). 717 1H NMR (400 MHz, Methanol-d4) δ 8.46 (d, J = 1.0 Hz, 1H), 8.31(d, J = 8.3 Hz, 1H), 8.25 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.62 (d, J= 2.3 Hz, 1H), 7.03 (d, J = 2.3 Hz, 1H), 6.38 (s, 1H), 5.94 (t, J = 54.5Hz, 1H), 3.99 (d, J = 14.0 Hz, 1H), 3.84 (d, J = 14.0 Hz, 1H), 2.75 (d,J = 7.7 Hz, 6H), 1.56 (s, 4H), 0.95 (d, J = 1.1 Hz, 9H). 718 1H NMR (400MHz, Methanol-d4) δ 8.47 (s, 1H), 8.06 (s, 1H), 7.71-7.58 (m, 2H), 7.26(d, J = 8.2 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 6.20 (s, 1H), 5.94 (t, J= 54.7 Hz, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.76 (d, J = 13.9 Hz, 1H),2.51 (s, 3H), 1.54 (d, J = 1.1 Hz, 4H), 0.92 (s, 9H). 719 1H NMR (400MHz, Methanol-d4) δ 8.50 (s, 1H), 7.90 (s, 1H), 7.74 (t, J = 8.1 Hz,1H), 7.62 (d, J = 2.3 Hz, 1H), 6.91-6.78 (m, 2H), 6.18 (s, 1H),4.41-4.14 (m, 2H), 2.69 (s, 1H), 2.51 (s, 3H), 2.37 (s, 6H), 1.14 (d, J= 3.3 Hz, 6H). 720 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.95(s, 1H), 7.74 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.94-6.80(m, 2H), 6.17 (s, 1H), 4.34 (d, J = 15.0 Hz, 1H), 4.20 (d, J = 15.0 Hz,1H), 2.49 (s, 3H), 1.65 (s, 3H), 1.31 (d, J = 5.2 Hz, 2H), 1.15 (d, J =2.2 Hz, 6H), 1.09-1.00 (m, 2H). 721 1H NMR (400 MHz, Methanol-d4) δ 8.44(s, 1H), 8.18 (s, 1H), 7.76 (t, J = 8.2 Hz, 1H), 7.61 (d, J = 2.3 Hz,1H), 6.95-6.74 (m, 2H), 6.22 (s, 1H), 4.29 (d, J = 14.9 Hz, 1H), 4.13(d, J = 14.9 Hz, 1H), 2.50 (s, 3H), 1.84-1.59 (m, 4H), 1.13 (d, J = 2.1Hz, 6H). 722 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.20 (s, 1H),7.84 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.93-6.77 (m, 1H),6.62 (d, J = 2.3 Hz, 1H), 6.11 (s, 1H), 4.53-4.20 (m, 2H), 3.04 (s, 3H),2.46 (s, 3H), 1.87-1.57 (m, 4H), 1.48 (s, 3H), 1.38 (s, 3H). 723 1H NMR(400 MHz, Methanol-d4) δ 8.43 (d, J = 3.3 Hz, 1H), 8.05 (d, J = 3.6 Hz,1H), 7.81 (q, J = 8.0 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.46-7.21 (m,5H), 7.14 (dd, J = 25.5, 2.3 Hz, 1H), 6.97-6.77 (m, 1H), 6.35 (d, J =5.8 Hz, 1H), 5.94 (td, J = 54.7, 8.7 Hz, 1H), 5.70 (dt, J = 20.5, 7.2Hz, 1H), 2.53 (d, J = 5.7 Hz, 3H), 2.12 (dh, J = 29.2, 7.2 Hz, 2H), 1.53(d, J = 6.7 Hz, 4H), 0.97 (dt, J = 14.5, 7.3 Hz, 3H). 724 1H NMR (400MHz, Methanol-d4) δ 8.50 (s, 1H), 8.35 (d, J = 8.1 Hz, 1H), 7.91 (s,1H), 7.74-7.61 (m, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz,1H), 6.94-6.74 (m, 2H), 6.57 (s, 1H), 5.92 (t, J = 54.7 Hz, 1H), 4.33(d, J = 14.8 Hz, 1H), 4.06 (d, J = 14.8 Hz, 1H), 1.58-1.40 (m, 4H), 1.01(d, J = 17.0 Hz, 6H). 725 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H),8.04 (s, 1H), 7.85-7.70 (m, 2H), 7.04 (d, J = 2.5 Hz, 1H), 6.87 (dd, J =8.4, 2.7 Hz, 1H), 6.21 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 4.21 (d, J =14.9 Hz, 1H), 4.05 (d, J = 14.9 Hz, 1H), 2.51 (s, 3H), 1.53 (t, J = 2.3Hz, 4H), 1.10 (d, J = 2.4 Hz, 6H). 726 1H NMR (400 MHz, Methanol-d4) δ8.52 (d, J = 1.3 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.92 (s, 1H),7.79-7.63 (m, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H),6.85 (d, J = 2.2 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 5.92(t, J = 54.7 Hz, 1H), 4.36 (d, J = 14.8 Hz, 1H), 4.05 (d, J = 14.8 Hz,1H), 1.50 (d, J = 5.1 Hz, 4H), 1.01 (d, J = 10.6 Hz, 6H). 727 1H NMR(400 MHz, Methanol-d4) δ 8.25 (s, 1H), 8.02 (s, 1H), 7.78 (t, J = 8.1Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 6.86 (dd, J = 8.5, 2.7 Hz, 1H), 6.71(d, J = 2.4 Hz, 1H), 6.19 (s, 1H), 5.95 (t, J = 54.8 Hz, 1H), 4.19 (d, J= 14.8 Hz, 1H), 3.99 (d, J = 14.8 Hz, 1H), 2.50 (s, 3H), 1.53 (q, J =2.1 Hz, 4H), 1.07 (d, J = 2.3 Hz, 6H). 728 1H NMR (400 MHz, Methanol-d4)δ 8.45 (s, 1H), 8.31 (s, 1H), 8.23 (dd, J = 7.9, 1.5 Hz, 1H), 7.92-7.86(m, 1H), 7.77 (s, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.52 (t, J = 7.8 Hz,1H), 6.98 (d, J = 2.4 Hz, 2H), 4.03 (d, J = 13.8 Hz, 1H), 3.73 (d, J =13.9 Hz, 1H), 3.59 (s, 3H), 2.66 (s, 1H), 2.34 (s, 6H), 0.86 (s, 9H).729 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.96 (s, 1H), 7.62 (d,J = 2.3 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H),6.61 (d, J = 8.6 Hz, 1H), 6.17 (s, 1H), 5.93 (t, J = 54.7 Hz, 1H), 4.00(d, J = 13.9 Hz, 1H), 3.89 (s, 4H), 2.48 (s, 3H), 1.52 (s, 4H), 0.94 (s,9H). 730 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.33 (d, J = 8.1Hz, 1H), 7.89 (s, 1H), 7.72 (dd, J = 7.2, 1.2 Hz, 1H), 7.65 (d, J = 2.3Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 6.89-6.71(m, 2H), 6.56 (s, 1H), 5.92 (t, J = 54.7 Hz, 1H), 4.52 (d, J = 14.9 Hz,1H), 4.09 (d, J = 14.8 Hz, 1H), 3.61 (s, 3H), 2.20-2.04 (m, 2H),2.04-1.76 (m, 3H), 1.68 (d, J = 8.8 Hz, 1H), 1.50 (t, J = 3.8 Hz, 4H).731 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.03 (s, 1H), 7.77 (t,J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.94-6.74 (m, 2H), 6.21 (s,1H), 5.94 (t, J = 54.7 Hz, 1H), 4.55 (d, J = 15.0 Hz, 1H), 4.28 (d, J =15.0 Hz, 1H), 2.49 (s, 3H), 2.32 (ddd, J = 12.5, 9.3, 6.6 Hz, 2H),2.19-1.77 (m, 4H), 1.64-1.46 (m, 4H). 732 1H NMR (400 MHz, Methanol-d4)δ 8.21 (d, J = 12.2 Hz, 1H), 8.05 (s, 1H), 7.51-7.34 (m, 2H), 6.79 (d, J= 2.4 Hz, 1H), 6.43 (dd, J = 15.8, 9.5 Hz, 1H), 6.08 (d, J = 9.5 Hz,1H), 3.80 (d, J = 13.8 Hz, 1H), 3.70-3.54 (m, 4H), 2.48 (s, 3H), 1.52(s, 4H), 0.90 (d, J = 2.4 Hz, 9H). 733 1H NMR (400 MHz, Methanol-d4) δ8.52 (s, 1H), 8.05 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.61 (d, J = 2.2Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.26(s, 1H), 5.94 (t, J = 54.6 Hz, 1H), 4.10 (dd, J = 14.6, 7.1 Hz, 1H),3.97 (dd, J = 14.6, 7.3 Hz, 1H), 2.50 (s, 3H), 1.54 (s, 4H), 1.11 (d, J= 3.7 Hz, 6H), 1.02 (d, J = 3.4 Hz, 6H), 0.79 (t, J = 7.2 Hz, 1H). 7341H NMR (400 MHz, Methanol-d4) δ 8.92 (s, 2H), 8.45 (s, 1H), 8.21-8.02(m, 2H), 7.97-7.88 (m, 1H), 7.83 (dd, J = 8.4, 7.3 Hz, 1H), 7.69 (d, J =2.3 Hz, 1H), 7.31 (s, 1H), 7.06 (d, J = 2.3 Hz, 1H), 3.99 (d, J = 13.8Hz, 1H), 3.69 (d, J = 13.9 Hz, 1H), 1.79-1.48 (m, 4H), 0.78 (s, 9H). 7351H NMR (400 MHz, Methanol-d4) δ 8.12 (s, 1H), 7.60 (d, J = 3.1 Hz, 1H),7.47 (dd, J = 7.2, 2.3 Hz, 1H), 7.29 (dt, J = 7.9, 1.0 Hz, 1H),7.22-7.03 (m, 3H), 6.65-6.49 (m, 2H), 6.28 (s, 1H), 3.76 (s, 3H),3.67-3.57 (m, 1H), 3.53-3.41 (m, 1H), 2.60 (s, 1H), 2.29 (s, 6H), 0.73(d, J = 1.4 Hz, 9H). 736 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H),7.80-7.60 (m, 2H), 7.36 (p, J = 3.8 Hz, 1H), 7.24-7.08 (m, 3H), 6.96 (d,J = 2.2 Hz, 1H), 6.54 (dd, J = 3.2, 0.9 Hz, 1H), 6.39 (s, 1H), 5.90 (t,J = 54.8 Hz, 1H), 4.05 (d, J = 13.7 Hz, 1H), 3.80 (s, 3H), 3.65 (d, J =13.8 Hz, 1H), 1.58-1.35 (m, 4H), 0.84 (s, 9H). 737 1H NMR (400 MHz,Methanol-d4) δ 8.44 (s, 1H), 8.04 (s, 1H), 7.80-7.57 (m, 3H), 7.50 (t, J= 7.6 Hz, 1H), 7.43-7.20 (m, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.21 (s,1H), 5.94 (t, J = 54.7 Hz, 1H), 4.69 (d, J = 18.0 Hz, 1H), 4.33 (d, J =18.0 Hz, 1H), 4.13 (d, J = 13.8 Hz, 1H), 3.70-3.56 (m, 1H), 3.15 (s,3H), 1.53 (d, J = 3.2 Hz, 4H), 0.85 (s, 9H). 738 1H NMR (400 MHz,Methanol-d4) δ 9.57 (s, 1H), 8.58 (d, J = 6.4 Hz, 1H), 8.50 (s, 1H),8.44 (d, J = 0.9 Hz, 1H), 8.24 (d, J = 6.4 Hz, 1H), 8.06 (s, 1H), 7.68(d, J = 2.3 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 6.61 (s, 1H), 4.01 (d, J= 14.0 Hz, 1H), 3.90 (tt, J = 7.4, 4.0 Hz, 1H), 3.82 (d, J = 14.0 Hz,1H), 1.24-1.13 (m, 4H), 0.88 (s, 9H). 739 1H NMR (400 MHz, Methanol-d4)δ 8.49 (s, 1H), 8.06 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 8.4, 2.8 Hz, 1H), 6.25(s, 1H), 5.93 (t, J = 54.6 Hz, 1H), 4.12 (m, 2H), 2.52 (s, 1H), 2.51 (s,3H), 1.80 (s, 6H), 1.54 (s, 4H). 740 1H NMR (400 MHz, Methanol-d4) δ8.49 (s, 1H), 8.20 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 8.5, 2.8 Hz, 1H), 6.26(s, 1H), 4.12 (s, 2H), 2.52 (s, 1H), 2.51 (s, 3H), 1.80 (s, 6H),1.78-1.72 (m, 2H), 1.72-1.65 (m, 2H). 741 1H NMR (400 MHz, Methanol-d4)δ 9.52 (s, 1H), 8.56 (d, J = 6.3 Hz, 1H), 8.48 (s, 1H), 8.38 (d, J = 1.0Hz, 1H), 8.32 (s, 1H), 8.20 (d, J = 6.3 1H), 7.68 (d, J = 2.3 Hz, 1H),7.17 (d, J = 2.3 Hz, 1H), 6.65 (s, 1H), 4.00 (d, J = 14.0 Hz, 1H), 3.80(d, J = 14.0 Hz, 1H), 1.81-1.71 (m, 2H), 1.69 (m, 2H), 0.87 (s, 9H). 7421H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.04 (s, 1H), 7.98 (t, J =2.1 Hz, 1H), 7.87-7.75 (m, 2H), 7.67 (d, J = 2.3 Hz, 1H), 7.10 (d, J =2.4 Hz, 1H), 6.88 (dd, J = 8.4, 2.7 Hz, 1H), 6.17 (s, 1H), 5.93 (t, J =54.7 Hz, 1H), 2.45 (s, 3H), 1.53 (s, 4H). 743 1H NMR (400 MHz,Methanol-d4) δ 8.48 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H),7.76 (d, J = 7.3 Hz, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.50 (t, J = 7.8 Hz,1H), 7.40 (d, J = 7.7 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.83 (d, J =7.9 Hz, 1H), 6.60 (s, 1H), 6.23 (tt, J = 56.0, 4.1 Hz, 1H), 5.92 (t, J =54.6 Hz, 1H), 4.56-4.43 (m, 1H), 4.44-4.28 (m, 1H), 4.04 (d, J = 13.8Hz, 1H), 3.64 (d, J = 13.8 Hz, 1H), 1.62-1.38 (m, 4H), 0.78 (s, 9H). 7441H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.34 (d, J = 8.1 Hz, 1H),7.91 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.48(t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H),6.82 (d, J = 7.8 Hz, 1H), 6.58 (s, 1H), 5.92 (t, J = 54.7 Hz, 1H), 4.02(d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 3.61 (s, 3H), 1.57-1.42(m, 4H), 0.78 (s, 9H). 745 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H),8.33 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.66(d, J = 2.3 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H),6.84 (d, J = 2.3 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.54 (s, 1H), 4.04(d, J = 13.8 Hz, 1H), 3.91-3.81 (m, 1H), 3.66 (d, J = 13.8 Hz, 1H), 3.61(s, 3H), 1.22-1.08 (m, 4H), 0.78 (s, 9H). 746 1H NMR (400 MHz,Methanol-d4) δ 8.51 (s, 1H), 8.06 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H),7.63 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.3, 2.8 Hz, 1H), 6.72 (d, J =2.2 Hz, 1H), 6.09 (s, 1H), 5.95 (t, J = 54.6 Hz, 1H), 4.09-3.95 (m, 2H),3.65-3.53 (m, 2H), 2.49 (s, 3H), 1.54 (s, 4H), 1.01 (s, 3H), 0.98 (s,3H). 747 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.39-8.28 (m,1H), 7.80 (s, 1H), 7.73 (dd, J = 7.5, 1.3 Hz, 1H), 7.65 (d, J = 2.2 Hz,1H), 7.47 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.89-6.73 (m,2H), 6.55 (s, 1H), 4.03 (d, J = 13.8 Hz, 1H), 3.63 (m, 4H), 1.61 (s,9H), 0.77 (s, 9H). 748 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H),7.90 (s, 1H), 7.83-7.73 (m, 2H), 7.10 (d, J = 2.5 Hz, 1H), 6.88 (dd, J =8.5, 2.7 Hz, 1H), 6.25 (s, 1H), 3.88 (d, J = 13.8 Hz, 1H), 3.65 (d, J =13.8 Hz, 1H), 2.50 (s, 3H), 1.65 (t, J = 18.7 Hz, 3H), 0.89 (s, 9H). 7491H NMR (400 MHz, Methanol-d4) δ 8.49 (d, J = 1.3 Hz, 1H), 7.90 (s, 1H),7.78 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 2.1 Hz,1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.25 (s, 1H), 4.94-4.82 (m, 1H),4.03 (d, J = 14.2 Hz, 1H), 3.81 (d, J = 14.0 Hz, 1H), 2.50 (s, 3H), 1.66(t, J = 18.7 Hz, 3H), 0.93 (s, 9H). 750 1H NMR (400 MHz, Methanol-d4) δ8.48 (s, 1H), 7.89 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.25(s, 1H), 4.90 (dd, J = 13.7, 2.8 Hz, 2H), 4.02 (d, J = 13.9 Hz, 1H),3.81 (d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 1.92 (td, J = 16.9, 8.3 Hz,2H), 1.05 (t, J = 7.5 Hz, 3H), 0.93 (s, 9H). 751 1H NMR (400 MHz,Methanol-d4) δ 8.50 (s, 1H), 7.92 (s, 1H), 7.74 (t, J = 8.1 Hz, 1H),7.64 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5,2.7 Hz, 1H), 6.24 (s, 1H), 4.64 (d, J = 1.3 Hz, 2H), 4.01 (d, J = 13.9Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 1.14 (s, 4H), 0.94 (s,9H). 752 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.88 (s, 1H),7.75 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 2.3 Hz,1H), 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.22 (s, 1H), 5.59 (t, J = 56.0 Hz,1H), 4.55 (s, 2H), 4.02 (d, J = 13.9 Hz, 1H), 3.86 (d, J = 13.9 Hz, 1H),2.50 (s, 3H), 0.94 (s, 14H). 753 1H NMR (400 MHz, Methanol-d4) δ 8.49(s, 1H), 8.01 (s, 1H), 7.72 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz,1H), 6.92 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.4, 2.8 Hz, 1H), 6.20 (s,1H), 3.99 (d, J = 14.0 Hz, 1H), 3.86 (d, J = 14.0 Hz, 1H), 2.86 (q, J =10.3 Hz, 2H), 2.48 (s, 3H), 1.52-1.23 (m, 4H), 0.93 (s, 9H). 754 1H NMR(400 MHz, Methanol-d4) δ 8.48 (s, 1H), 7.95 (s, 1H), 7.76 (t, J = 8.1Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.00-6.78 (m, 2H), 6.19 (s, 1H), 4.00(d, J = 13.9 Hz, 1H), 3.83 (d, J = 14.0 Hz, 1H), 2.49 (s, 3H), 1.92-1.74(m, 2H), 1.31-1.17 (m, 2H), 1.06 (d, J = 1.8 Hz, 2H), 0.93 (s, 9H), 0.82(t, J = 7.4 Hz, 3H). 755 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H),7.88 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.94(d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.4, 2.8 Hz, 1H), 6.23 (s, 1H), 4.55(s, 2H), 4.01 (d, J = 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.49 (s,3H), 1.17 (d, J = 6.7 Hz, 6H), 0.94 (s, 9H). 756 1H NMR (400 MHz,Methanol-d4) δ 8.46 (s, 1H), 8.33 (d, J = 8.3 Hz, 1H), 7.80 (s, 1H),7.76-7.68 (m, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H),7.40 (d, J = 7.7 Hz, 1H), 6.88-6.75 (m, 2H), 6.54 (s, 1H), 4.01 (d, J =13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 3.60 (s, 3H), 1.83 (q, J = 7.4Hz, 2H), 1.21 (d, J = 5.5 Hz, 2H), 1.13-0.97 (m, 2H), 0.78 (d, J = 7.6Hz, 12H). 757 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.91 (s,1H), 7.76 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.93 (d, J =2.3 Hz, 1H), 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.21 (s, 1H), 4.03 (d, J =13.9 Hz, 1H), 3.85 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.65 (p, J = 6.8Hz, 1H), 1.24-1.15 (m, 2H), 1.15-1.08 (m, 2H), 0.94 (s, 9H), 0.93-0.87(m, 6H). 758 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 7.97 (s, 1H),7.78 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.90-6.87 (m, 1H),6.87-6.85 (m, 1H), 6.20 (s, 1H), 4.02 (d, J = 13.9 Hz, 1H), 3.81 (d, J =13.9 Hz, 1H), 2.49 (s, 3H), 1.57 (s, 3H), 1.56 (s, 3H), 1.39-1.31 (m,1H), 0.93 (s, 9H), 0.56-0.49 (m, 2H), 0.46-0.38 (m, 2H). 759 1H NMR (400MHz, Methanol-d4) δ 8.50 (s, 1H), 8.07 (s, 1H), 7.80 (t, J = 8.1 Hz,1H), 7.63 (d, J = 2.3 Hz, 1H), 6.95-6.84 (m, 2H), 6.24 (s, 1H), 5.09 (t,J = 6.3 Hz, 2H), 4.75 (dd, J = 6.8, 2.3 Hz, 2H), 4.02 (d, J = 13.9 Hz,1H), 3.84 (d, J = 13.9 Hz, 1H), 2.51 (s, 3H), 1.92 (s, 3H), 0.93 (s,9H). 760 1H NMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.34 (d, J = 8.0Hz, 1H), 7.92 (s, 1H), 7.75 (dd, J = 7.5, 1.0 Hz, 1H), 7.66 (d, J = 2.3Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.87-6.80(m, 2H), 6.58 (s, 1H), 5.06 (dd, J = 6.8, 4.2 Hz, 2H), 4.76-4.69 (m,2H), 4.02 (d, J = 13.8 Hz, 1H), 3.64 (d, J = 13.8 Hz, 1H), 3.61 (s, 3H),1.88 (s, 3H), 0.77 (s, 9H). 761 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s,1H), 7.90 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H),6.92 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.6, 2.8 Hz, 1H), 6.20 (s, 1H),4.01 (d, J = 13.9 Hz, 1H), 3.85 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.28(m, 2H), 1.08 (m, 2H), 0.94 (s, 9H), 0.88 (s, 9H). 762 1H NMR (400 MHz,Methanol-d4) δ 8.48 (s, 1H), 8.02 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H),7.64 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5,2.8 Hz, 1H), 6.25 (s, 1H), 5.39-5.21 (m, 1H), 5.05-4.91 (m, 2H), 4.84(s, 2H), 4.02 (d, J = 13.9 Hz, 1H), 3.81 (d, J = 13.9 Hz, 1H), 2.50 (s,3H), 0.93 (s, 9H). 763 1H NMR (400 MHz, Methanol-d4) δ 8.54 (s, 1H),8.00 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.88(d, J = 2.8 Hz, 1H), 6.86 (d, J = 2.2 Hz, 2H), 6.18 (s, 1H), 4.37 (d, J= 15.0 Hz, 1H), 4.18 (d, J = 15.0 Hz, 1H), 2.49 (s, 3H), 1.59-1.49 (m,1H), 1.30-1.19 (m, 2H), 1.15 (s, 3H), 1.15 (s, 3H), 1.08-0.96 (m, 2H),0.57-0.48 (m, 2H), 0.37-0.27 (m, 2H). 764 1H NMR (400 MHz, Methanol-d4)δ 8.49 (s, 1H), 7.87 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.22(s, 1H), 4.23 (d, J = 3.1 Hz, 2H), 4.04 (d, J = 13.9 Hz, 1H), 3.81 (d, J= 13.9 Hz, 1H), 2.50 (s, 3H), 0.96 (s, 3H), 0.93 (s, 9H), 0.71-0.66 (m,2H), 0.43 (m, 2H). 765 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H),8.33 (d, J = 7.9 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.67(d, J = 2.3 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H),6.84 (d, J = 2.2 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.59 (s, 1H), 5.92(t, J = 54.7 Hz, 1H), 4.02 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz,1H), 1.51 (s, 4H), 0.79 (s, 9H). 766 1H NMR (400 MHz, Methanol-d4) δ8.50 (s, 1H), 7.84 (s, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 2.3Hz, 1H), 6.90 (d, J = 2.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.19 (s,1H), 4.21-4.14 (m, 1H), 4.02 (d, J = 14.0 Hz, 1H), 3.83 (d, J = 13.9 Hz,1H), 2.49 (s, 3H), 1.75-1.67 (m, 2H), 1.17-1.12 (m, 1H), 1.06-0.95 (m,1H), 0.95-0.91 (m, 1H), 0.93 (s, 9H), 0.90-0.74 (m, 1H). 767 1H NMR (400MHz, Methanol-d4) δ 8.47 (s, 1H), 8.22 (d, J = 5.0 Hz, 1H), 7.94 (s,1H), 7.70 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 3.5 Hz, 1H), 7.25 (d, J =5.2 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), 6.50(s, 1H), 5.91 (t, J = 54.7 Hz, 1H), 4.14 (d, J = 13.8 Hz, 1H), 3.86 (s,3H), 3.60 (d, J = 13.8 Hz, 1H), 1.56-1.39 (m, 4H), 0.82 (s, 9H). 768 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H),7.79 (s, 1H), 7.74-7.67 (m, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.48 (t, J =7.8 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.70(d, J = 2.3 Hz, 1H), 6.42 (s, 1H), 4.01 (d, J = 13.3 Hz, 1H), 3.90 (d, J= 13.4 Hz, 1H), 3.61 (s, 3H), 3.48 (d, J = 10.5 Hz, 1H), 3.40 (d, J =10.5 Hz, 1H), 2.68 (s, 1H), 2.35 (s, 6H), 0.91 (s, 3H), 0.81 (s, 3H).769 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 8.33 (d, J = 8.2 Hz,1H), 7.75 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H),7.47 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.8 Hz,1H), 6.80-6.75 (m, 1H), 6.55 (s, 1H), 4.15-4.03 (m, 2H), 4.00 (d, J =13.8 Hz, 1H), 3.59 (d, J = 13.7 Hz, 1H), 2.67 (s, 1H), 2.34 (s, 6H),1.36 (t, J = 7.1 Hz, 3H), 0.74 (s, 9H). 770 1H NMR (400 MHz,Methanol-d4) δ 8.49 (s, 1H), 8.39-8.32 (m, 1H), 8.06 (s, 1H), 7.80-7.73(m, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.39 (d, J= 7.8 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.61(s, 1H), 6.39-6.05 (m, 1H), 4.55-4.32 (m, 2H), 4.04 (d, J = 13.8 Hz,1H), 3.66 (d, J = 13.8 Hz, 1H), 1.75-1.56 (m, 4H), 0.78 (s, 9H). 771 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.36 (d, J = 8.1 Hz, 1H),8.07 (s, 1H), 7.81-7.73 (m, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.52 (t, J =7.8 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.83(d, J = 7.8 Hz, 1H), 6.61 (s, 1H), 5.03-4.84 (m, 1H), 4.81-4.66 (m, 1H),4.06 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.9 Hz, 1H), 1.84-1.53 (m, 4H),0.78 (s, 9H). 772 1H NMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.34 (d,J = 8.1 Hz, 1H), 7.75 (s, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.65 (d, J =2.2 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 6.87(d, J = 7.9 Hz, 1H), 6.79 (d, J = 2.3 Hz, 1H), 6.56 (s, 1H), 5.29 (p, J= 6.8 Hz, 1H), 4.04 (d, J = 13.7 Hz, 1H), 3.58 (d, J = 13.8 Hz, 1H),2.67 (s, 1H), 2.34 (s, 6H), 1.42 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 6.8Hz, 3H), 0.73 (s, 9H). 773 1H NMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H),8.37-8.30 (m, 1H), 7.82 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.65 (d, J =2.3 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 6.83(d, J = 7.8 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 6.54 (s, 1H), 4.17-3.98(m, 2H), 4.03 (d, J = 13.8 Hz, 1H), 3.61 (d, J = 13.8 Hz, 1H), 1.62 (s,3H), 1.36 (t, J = 7.1 Hz, 3H), 1.32-1.22 (m, 2H), 1.06-1.00 (m, 2H),0.75 (s, 9H). 774 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H),8.38-8.30 (m, 1H), 7.81 (s, 1H), 7.73 (d, J = 7.3 Hz, 1H), 7.63 (d, J =2.3 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 6.88(d, J = 7.8 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.54 (s, 1H), 5.36-5.22(m, 1H), 4.01 (d, J = 13.8 Hz, 1H), 3.57 (d, J = 13.8 Hz, 1H), 1.62 (s,3H), 1.42 (d, J = 6.9 Hz, 3H), 1.40 (d, J = 6.9 Hz, 3H), 1.32-1.25 (m,2H), 1.07-0.99 (m, 2H), 0.73 (s, 9H). 775 1H NMR (400 MHz, Methanol-d4)δ 8.48 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.88 (s, 1H), 7.73(d, J = 7.4 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H),7.41 (d, J = 7.7 Hz, 1H), 6.87-6.79 (m, 2H), 6.57 (s, 1H), 4.59 (d, J =48.4 Hz, 2H), 4.05 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 3.61(s, 3H), 1.46-1.29 (m, 4H), 0.77 (s, 9H). 776 1H NMR (400 MHz,Methanol-d4) δ 8.50 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.83 (s, 1H),7.72 (d, J = 7.4 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.48 (t, J = 7.8 Hz,1H), 7.41 (d, J = 7.7 Hz, 1H), 6.85-6.77 (m, 2H), 6.54 (s, 1H), 4.06 (d,J = 13.9 Hz, 1H), 3.64 (d, J = 13.6 Hz, 1H), 3.61 (s, 3H), 1.62 (s, 3H),1.30-1.26 (m, 2H), 1.07-1.01 (m, 2H), 0.76 (s, 9H). 777 1H NMR (400 MHz,Methanol-d4) δ 8.48 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.88 (s, 1H),7.77-7.70 (m, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H),7.42 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.82 (d, J = 7.6 Hz,1H), 6.61 (s, 1H), 5.24 (t, J = 19.1 Hz, 1H), 5.02-4.91 (m, 2H),4.87-4.69 (m, 2H), 4.05 (d, J = 13.8 Hz, 1H), 3.64 (d, J = 13.7 Hz, 1H),3.61 (s, 3H), 0.77 (s, 9H). 778 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s,1H), 8.34 (d, J = 8.2 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H),7.67 (d, J = 2.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz,1H), 6.85 (d, J = 2.3 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.58 (s, 1H),5.05-4.91 (m, 1H), 4.67 (d, J = 46.9 Hz, 1H), 4.66 (d, J = 47.0 Hz, 1H),4.06 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 3.61 (s, 3H), 1.53(dd, J = 7.1, 1.2 Hz, 3H), 0.77 (s, 9H). 779 1H NMR (400 MHz,Methanol-d4) δ 8.18 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H),7.44 (d, J = 7.3 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.18 (t, J = 7.8 Hz,1H), 7.12 (d, J = 7.7 Hz, 1H), 6.55-6.48 (m, 2H), 6.25 (s, 1H), 3.76 (d,J = 13.6 Hz, 1H), 3.33 (d, J = 14.0 Hz, 1H), 3.31 (s, 3H), 1.26-1.17 (m,1H), 0.98-0.81 (m, 2H), 0.79-0.62 (m, 2H), 0.47 (s, 9H), 0.27-0.13 (m,2H), 0.12-−0.09 (m, 2H). 780 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s,1H), 8.35 (d, J = 8.3 Hz, 1H), 8.07 (s, 1H), 7.72-7.68 (m, 1H), 7.67 (d,J = 2.3 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H),6.85 (d, J = 2.3 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 4.34(d, J = 14.9 Hz, 1H), 4.07 (d, J = 14.9 Hz, 1H), 3.61 (s, 3H), 1.85-1.55(m, 4H), 1.02 (d, J = 16.4 Hz, 6H). 781 1H NMR (400 MHz, Methanol-d4) δ8.52 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 7.84 (s, 1H), 7.72-7.67 (m, 1H),7.66 (d, J = 2.3 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz,1H), 6.82 (d, J = 2.3 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.53 (s, 1H),4.35 (d, J = 14.9 Hz, 1H), 4.07 (d, J = 14.9 Hz, 1H), 3.61 (s, 3H), 1.63(s, 3H), 1.32-1.25 (m, 2H), 1.06-1.01 (m, 5H), 0.99 (s, 3H). 782 1H NMR(400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.14 (s, 1H), 8.12 (dd, J = 5.0,1.9 Hz, 1H), 7.68 (dd, J = 7.3, 1.9 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H),7.06 (d, J = 2.3 Hz, 1H), 6.95 (dd, J = 7.4, 5.0 Hz, 1H), 6.29 (s, 1H),4.05 (d, J = 13.9 Hz, 1H), 3.94 (s, 3H), 3.85 (d, J = 13.9 Hz, 1H),1.82-1.59 (m, 4H), 0.97 (s, 9H). 783 1H NMR (400 MHz, Methanol-d4) δ8.18 (s, 1H), 8.08-8.00 (m, 1H), 7.57 (s, 1H), 7.46-7.38 (m, 1H), 7.35(d, J = 2.3 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H),6.54-6.46 (m, 2H), 6.23 (s, 1H), 4.03 (d, J = 14.8 Hz, 1H), 3.71 (d, J =14.9 Hz, 1H), 3.31 (s, 3H), 1.21 (ddd, J = 13.1, 8.1, 4.9 Hz, 1H),0.97-0.79 (m, 2H), 0.69 (d, J = 18.4 Hz, 6H), 0.71-0.68 (m, 2H),0.25-0.15 (m, 2H), 0.01 (t, J = 5.0 Hz, 2H). 784 1H NMR (400 MHz,Methanol-d4) δ 9.85 (s, 1H), 9.71 (d, J = 7.9 Hz, 1H), 9.17 (s, 1H),9.07 (d, J = 7.5 Hz, 1H), 9.02 (s, 1H), 8.85 (t, J = 8.0 Hz, 1H), 8.78(d, J = 7.6 Hz, 1H), 8.18 (s, 2H), 7.93 (s, 1H), 6.46-6.27 (m, 1H), 6.03(dd, J = 46.9, 5.4 Hz, 2H), 5.70 (d, J = 14.8 Hz, 1H), 5.40 (d, J = 14.8Hz, 1H), 4.98 (s, 3H), 2.90 (d, J = 7.0 Hz, 3H), 2.36 (d, J = 17.8 Hz,6H). 785 1H NMR (400 MHz, Methanol-d4) δ 9.84 (s, 1H), 9.70 (d, J = 8.3Hz, 1H), 9.14 (s, 1H), 9.05 (d, J = 7.5 Hz, 1H), 9.00 (d, J = 2.2 Hz,1H), 8.84 (t, J = 7.8 Hz, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.28-8.05 (m,2H), 7.90 (s, 1H), 5.66 (d, J = 14.9 Hz, 1H), 5.41 (d, J = 14.8 Hz, 1H),4.97 (s, 3H), 4.03 (s, 1H), 3.71 (s, 6H), 2.36 (d, J = 18.1 Hz, 6H). 7861H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.17 (d, J = 9.9 Hz, 1H),7.78 (s, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.64-7.59 (m, 2H), 7.40-7.33 (m,1H), 6.83 (d, J = 2.3 Hz, 1H), 6.71 (d, J = 9.9 Hz, 1H), 6.65 (s, 1H),4.07 (d, J = 13.9 Hz, 1H), 3.77 (s, 3H), 3.61 (d, J = 13.9 Hz, 1H), 2.67(s, 1H), 2.35 (s, 6H), 0.77 (s, 9H). 787 1H NMR (400 MHz, Methanol-d4) δ8.46 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 7.77-7.72 (m, 2H), 7.65 (d, J =2.3 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 6.81(dd, J = 5.0, 2.6 Hz, 2H), 6.56 (s, 1H), 4.01 (d, J = 13.8 Hz, 1H), 3.63(d, J = 13.8 Hz, 1H), 2.67 (s, 1H), 2.35 (s, 6H), 0.77 (s, 9H). 788 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H),8.11 (s, 1H), 7.91 (t, J = 60.1 Hz, 1H), 7.83-7.79 (m, 1H), 7.69 (d, J =2.3 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 6.92(d, J = 8.1 Hz, 1H), 6.86 (d, J = 2.3 Hz, 1H), 6.62 (s, 1H), 4.07 (d, J= 13.8 Hz, 1H), 3.64 (d, J = 13.8 Hz, 1H), 1.85-1.51 (m, 4H), 0.79 (s,9H). 789 1H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.17 (d, J = 9.8Hz, 1H), 8.08 (s, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.64 (s, 1H), 7.63 (d,J = 2.4 Hz, 1H), 7.37 (dd, J = 5.5, 3.1 Hz, 1H), 6.87 (d, J = 2.3 Hz,1H), 6.72 (d, J = 9.8 Hz, 1H), 6.70 (s, 1H), 4.08 (d, J = 13.9 Hz, 1H),3.78 (s, 3H), 3.61 (d, J = 13.8 Hz, 1H), 1.77-1.59 (m, 4H), 0.77 (s,9H). 790 1H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.40-8.26 (m,1H), 7.74 (dd, J = 7.6, 1.2 Hz, 1H), 7.66 (d, J = 2.0 Hz, 2H), 7.47 (t,J = 7.8 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 6.88-6.75 (m, 2H), 6.54 (s,1H), 4.03 (m, 4H), 3.71-3.55 (m, 4H), 0.77 (s, 9H). 791 1H NMR (400 MHz,Methanol-d4) δ 8.20 (s, 1H), 7.89-7.70 (m, 2H), 7.48 (d, J = 2.4 Hz,1H), 6.86 (dd, J = 8.4, 2.7 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.16 (s,1H), 4.07 (s, 3H), 3.79 (d, J = 13.7 Hz, 1H), 3.59 (d, J = 13.8 Hz, 1H),2.51 (s, 3H), 0.86 (s, 9H). 792 1H NMR (400 MHz, Methanol-d4) δ 8.50 (d,J = 1.0 Hz, 1H), 8.19 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.62 (d, J =2.3 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H),6.24 (s, 1H), 4.53 (dd, J = 12.1, 6.4 Hz, 2H), 4.43 (t, J = 6.1 Hz, 2H),4.12 (s, 2H), 2.50 (s, 3H), 1.81-1.56 (m, 4H), 1.39 (s, 3H). 793 1H NMR(400 MHz, Methanol-d4) δ 8.47 (d, J = 3.1 Hz, 2H), 8.23 (s, 1H), 7.89(dd, J = 8.3, 2.6 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 8.3Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.20 (s, 1H), 4.15 (d, J = 14.0 Hz,1H), 3.73 (d, J = 14.0 Hz, 1H), 1.80-1.72 (m, 2H), 1.69 (d, J = 9.1 Hz,2H), 0.96 (s, 9H). 794 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H),8.21 (s, 1H), 7.70-7.60 (m, 2H), 7.27 (d, J = 8.2 Hz, 1H), 6.89 (d, J =2.3 Hz, 1H), 6.22 (s, 1H), 4.05 (d, J = 13.9 Hz, 1H), 3.77 (d, J = 13.9Hz, 1H), 2.51 (s, 3H), 1.81-1.61 (m, 4H), 0.92 (s, 9H). 795 1H NMR (400MHz, Methanol-d4) δ 8.71 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.31 (s,1H), 8.28 (dd, J = 8.3, 2.3 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.67 (d,J = 2.3 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 6.33 (s, 1H), 4.09 (d, J =14.0 Hz, 1H), 3.81 (d, J = 14.0 Hz, 1H), 2.69 (s, 3H), 1.80-1.73 (m,2H), 1.72-1.62 (m, 2H), 0.97 (s, 9H). 796 1H NMR (400 MHz,Acetonitrile-d3) δ 8.39 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.79 (d, J =7.2 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.45 (t, J = 7.8Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.60 (s,1H), 6.46 (s, 1H), 5.07-4.98 (m, 1H), 3.77-3.69 (m, 1H), 3.62 (m, 1H),3.54 (s, 3H), 2.54-2.44 (m, 4H), 1.89 (m, 2H), 0.79 (s, 9H). 797 1H NMR(400 MHz, Methanol-d4) δ 9.03 (d, J = 4.5 Hz, 1H), 8.87 (d, J = 8.6 Hz,1H), 8.45 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.95-7.83 (m, 2H),7.82-7.73 (m, 2H), 7.66 (d, J = 2.3 Hz, 1H), 6.85-6.79 (m, 2H), 4.30 (d,J = 14.9 Hz, 1H), 3.93 (d, J = 14.9 Hz, 1H), 1.62 (s, 3H), 1.30 (d, J =13.3 Hz, 2H), 1.03 (s, 2H), 0.94 (s, 3H), 0.88 (s, 3H). 798 1H NMR (400MHz, Methanol-d4) δ 9.02 (d, J = 4.9 Hz, 1H), 8.85 (d, J = 8.4 Hz, 1H),8.44 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.87 (t, J = 7.9Hz, 1H), 7.81-7.72 (m, 2H), 7.67 (d, J = 2.3 Hz, 1H), 6.86-6.79 (m, 2H),4.31 (d, J = 14.8 Hz, 1H), 3.91 (d, J = 14.9 Hz, 1H), 1.18 (s, 2H), 0.99(s, 2H), 0.94 (s, 3H), 0.88 (s, 3H), 0.49 (d, J = 7.5 Hz, 2H), 0.29 (d,J = 5.1 Hz, 2H). 799 1H NMR (400 MHz, Methanol-d4) δ 9.05 (d, J = 4.6Hz, 1H), 8.92 (d, J = 8.7 Hz, 1H), 8.48 (s, 1H), 8.12 (d, J = 8.6 Hz,1H), 7.94-7.85 (m, 2H), 7.85-7.76 (m, 2H), 7.67 (d, J = 2.3 Hz, 1H),6.88-6.81 (m, 2H), 4.31 (d, J = 14.9 Hz, 1H), 3.96 (d, J = 14.9 Hz, 1H),2.67 (s, 1H), 2.34 (s, 6H), 0.95 (s, 3H), 0.90 (s, 3H). 800 (1H NMR (400MHz, Acetonitrile-d3) δ 8.38 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.80 (d,J = 7.5 Hz, 1H), 7.65 (s, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.45 (t, J =7.7 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.58(s, 1H), 6.46 (s, 1H), 3.77-3.67 (m, 1H), 3.61 (m, 1H), 3.54 (s, 3H),2.68 (d, J = 10.2 Hz, 2H), 2.5, (m, 2H), 2.27 (s, 2H), 1.69 (s, 3H),0.78 (s, 9H). 801 1H NMR (400 MHz, Acetonitrile-d3) δ 8.40 (s, 1H), 8.31(d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.56 (dd, J = 21.4, 1.8Hz, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 6.81-6.74(m, 1H), 6.61 (s, 1H), 6.47 (s, 1H), 3.84-3.68 (m, 1H), 3.63 (m, 1H),3.54 (s, 3H), 1.86-1.78 (m, 2H), 1.46 (dd, J = 6.8, 3.3 Hz, 3H), 0.79(d, J = 1.1 Hz, 9H), 0.78-0.69 (m, 3H). 802 1H NMR (400 MHz,Acetonitrile-d3) δ 8.39 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.83-7.76 (m,1H), 7.63 (s, 1H), 7.54 (d, J = 2.3 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H),7.31 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.61 (s, 1H), 6.47(s, 1H), 6.24 (s, 1H), 4.79 (m, 1H), 3.76 (m, 1H), 3.71-3.53 (m, 3H),3.54 (s, 3H), 3.20 (s, 3H), 1.45 (d, J = 6.9 Hz, 3H), 0.80 (s, 9H). 8031H NMR (400 MHz, Methanol-d4) δ 8.98 (d, J = 4.6 Hz, 1H), 8.78 (d, J =8.6 Hz, 1H), 8.46 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.89-7.79 (m, 2H),7.79-7.65 (m, 3H), 6.95-6.85 (m, 2H), 4.96 (dd, J = 12.2, 5.9 Hz, 1H),4.71 (d, J = 5.4 Hz, 1H), 4.60 (d, J = 5.4 Hz, 1H), 4.00 (d, J = 13.8Hz, 1H), 3.61 (d, J = 13.9 Hz, 1H), 1.52 (dd, J = 7.1, 1.3 Hz, 3H), 0.69(s, 9H). 804 1H NMR (400 MHz, Methanol-d4) δ 8.98 (d, J = 4.5 Hz, 1H),8.78 (d, J = 8.7 Hz, 1H), 8.46 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.94(s, 1H), 7.88-7.79 (m, 1H), 7.79-7.66 (m, 3H), 6.96-6.88 (m, 2H), 5.22(s, 1H), 4.99-4.84 (m, 3H), 4.84-4.73 (m, 1H), 4.00 (d, J = 13.9 Hz,1H), 3.61 (d, J = 13.8 Hz, 1H), 0.69 (s, 9H). 805 1H NMR (400 MHz,Methanol-d4) δ 8.47 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.74 (dd, J =8.7, 2.5 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.10 (s, 1H), 6.81 (d, J =8.7 Hz, 1H), 6.10 (s, 1H), 4.12 (d, J = 14.0 Hz, 1H), 3.89 (s, 3H), 3.79(d, J = 14.0 Hz, 1H), 1.83-1.56 (m, 4H), 0.98 (s, 9H). 806 1H NMR (400MHz, Methanol-d4) δ 8.54 (s, 1H), 8.20 (s, 1H), 7.84 (t, J = 8.1 Hz,1H), 7.64 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.88 (dd, J =8.7, 2.8 Hz, 1H), 6.25 (s, 1H), 4.12 (d, J = 13.9 Hz, 1H), 3.81 (d, J =13.9 Hz, 1H), 2.52 (s, 3H), 2.46 (s, 3H), 2.06-1.93 (m, 4H), 0.94 (s,9H). 807 1H NMR (400 MHz, Methanol-d4) δ 8.27 (s, 1H), 8.23 (d, J = 8.3Hz, 1H), 7.95 (d, J = 6.2 Hz, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.72 (s,2H), 7.51 (d, J = 7.8 Hz, 1H), 7.49-7.42 (m, 2H), 6.93 (d, J = 2.5 Hz,1H), 6.66 (s, 1H), 4.09 (s, 3H), 3.71 (d, J = 13.5 Hz, 1H), 3.44 (d, J =13.6 Hz, 1H), 2.30 (s, 6H), 0.61 (s, 9H). 808 1H NMR (400 MHz,Methanol-d4) δ 8.28 (s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.95 (dd, J =6.3, 1.4 Hz, 1H), 7.77-7.70 (m, 4H), 7.53-7.44 (m, 2H), 6.94 (d, J = 2.4Hz, 1H), 6.64 (s, 1H), 4.09 (d, J = 1.4 Hz, 3H), 3.85-3.77 (m, 0H), 3.72(d, J = 13.4 Hz, 1H), 3.45 (d, J = 13.2 Hz, 1H), 1.16-1.04 (m, 4H), 0.62(d, J = 1.4 Hz, 9H). 809 1H NMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H),8.22 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.79 (s, 1H), 7.75(d, J = 2.3 Hz, 1H), 7.73 (s, 1H), 7.54-7.43 (m, 2H), 6.92 (d, J = 2.5Hz, 1H), 6.64 (s, 1H), 4.09 (d, J = 1.0 Hz, 3H), 3.71 (d, J = 13.4 Hz,1H), 3.44 (d, J = 13.8 Hz, 1H), 1.58 (s, 3H), 1.24 (s, 3H), 1.01-0.96(m, 2H), 0.61 (d, J = 1.0 Hz, 8H). 810 1H NMR (400 MHz, Methanol-d4) δ8.29 (d, J = 1.4 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.98-7.93 (m, 1H),7.87 (s, 1H), 7.79-7.76 (m, 1H), 7.74 (d, J = 7.3 Hz, 1H), 7.54-7.44 (m,3H), 6.98 (d, J = 2.5 Hz, 1H), 6.69 (s, 1H), 5.88 (t, J = 55.0 Hz, 1H),4.09 (d, J = 1.2 Hz, 3H), 3.75 (d, J = 13.6 Hz, 1H), 3.47 (d, J = 13.5Hz, 1H), 1.46 (d, J = 1.2 Hz, 2H), 0.63 (d, J = 1.1 Hz, 10H). 811 1H NMR(400 MHz, Methanol-d4) δ 8.39 (d, J = 9.2 Hz, 1H), 8.36 (s, 1H), 8.04(s, 1H), 7.82 (s, 1H), 7.82 (d, J = 10.3 Hz, 1H), 7.59 (t, J = 8.5, 7.4Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H), 7.00 (d, J= 9.2 Hz, 1H), 6.78 (s, 1H), 4.06 (d, J = 0.6 Hz, 3H), 3.83 (d, J = 13.7Hz, 1H), 3.55 (d, J = 13.7 Hz, 1H), 1.76-1.56 (m, 5H), 0.69 (s, 9H). 8121H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H),8.07 (s, 1H), 7.99 (d, J = 6.2 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.77(d, J = 7.2 Hz, 1H), 7.58-7.51 (m, 1H), 7.49 (d, J = 6.4 Hz, 1H), 7.04(d, J = 2.5 Hz, 1H), 6.75 (s, 1H), 4.13 (s, 3H), 3.82 (d, J = 13.7 Hz,1H), 3.52 (d, J = 13.7 Hz, 1H), 1.77-1.55 (m, 4H), 0.66 (s, 9H). 814 1HNMR (400 MHz, Methanol-d4) δ 8.95 (dd, J = 4.4, 1.4 Hz, 1H), 8.67 (d, J= 8.8 Hz, 1H), 8.35 (s, 1H), 7.86 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H),7.69 (dd, J = 8.7, 4.3 Hz, 1H), 7.64 (dd, J = 8.2, 4.8 Hz, 1H), 7.48(dd, J = 10.3, 8.2 Hz, 1H), 7.06 (d, J = 2.5 Hz, 1H), 6.78 (s, 1H), 3.82(d, J = 13.7 Hz, 1H), 3.49 (d, J = 13.8 Hz, 1H), 2.66 (s, 1H), 2.34 (s,6H), 0.64 (s, 9H). 815 1H NMR (400 MHz, Methanol-d4) δ 8.96 (d, J = 4.3Hz, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.81 (d,J = 2.5 Hz, 1H), 7.71 (dd, J = 8.7, 4.4 Hz, 1H), 7.63 (dd, J = 8.2, 4.8Hz, 1H), 7.50 (dd, J = 10.0, 8.5 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.78(s, 1H), 5.91 (t, J = 54.7 Hz, 1H), 4.16 (d, J = 14.8 Hz, 1H), 3.86 (d,J = 14.8 Hz, 1H), 1.49 (d, J = 5.4 Hz, 4H), 0.90 (s, 3H), 0.85 (s, 3H).816 1H NMR (400 MHz, Methanol-d4) δ 8.95 (d, J = 4.3 Hz, 1H), 8.66 (d, J= 8.7 Hz, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.79 (d, J = 2.4 Hz, 1H),7.69 (dd, J = 8.8, 4.3 Hz, 1H), 7.61 (dd, J = 8.2, 4.8 Hz, 1H),7.52-7.44 (m, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.75 (s, 1H), 4.14 (d, J =14.8 Hz, 1H), 3.85 (d, J = 14.8 Hz, 1H), 2.66 (s, 1H), 2.34 (s, 6H),2.02 (s, 1H), 0.88 (s, 3H), 0.83 (s, 3H). 817 1H NMR (400 MHz,Methanol-d4) δ 8.67 (d, J = 5.9 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.30(s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.89-7.83(m, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.88 (s,1H), 3.80 (d, J = 13.7 Hz, 1H), 3.43 (d, J = 13.7 Hz, 1H), 1.76-1.56 (m,4H), 0.62 (s, 9H). 818 1H NMR (400 MHz, Methanol-d4) δ 9.02 (dd, J =5.0, 1.6 Hz, 1H), 8.84 (d, J = 8.3 Hz, 1H), 8.29 (s, 1H), 8.22 (s, 1H),8.19 (s, 1H), 8.12 (s, 1H), 7.93 (dd, J = 8.7, 1.7 Hz, 1H), 7.89-7.81(m, 2H), 7.22 (d, J = 2.5 Hz, 1H), 6.41 (s, 1H), 5.95 (t, J = 54.6 Hz,1H), 3.91 (d, J = 13.9 Hz, 1H), 3.47 (d, J = 13.9 Hz, 1H), 1.54 (s, 4H),0.72 (s, 9H). 819 1H NMR (400 MHz, Methanol-d4) δ 8.32 (s, 1H), 8.26 (d,J = 8.3 Hz, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J =2.4 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.48(d, J = 6.3 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.66 (s, 1H), 4.12 (d, J= 14.8 Hz, 1H), 4.12 (s, 3H), 3.85 (d, J = 14.7 Hz, 1H), 1.62 (s, 3H),1.27 (d, J = 5.6 Hz, 2H), 1.07-0.99 (m, 2H), 0.84 (d, J = 13.7 Hz, 6H).820 1H NMR (400 MHz, Methanol-d4) δ 8.32 (s, 1H), 8.26 (d, J = 8.3 Hz,1H), 7.99 (d, J = 6.2 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.76 (s, 1H),7.72 (d, J = 7.3 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 6.2 Hz,1H), 6.96 (d, J = 2.5 Hz, 1H), 6.67 (s, 1H), 4.10 (d, J = 12.8 Hz, 4H),3.86 (d, J = 14.6 Hz, 1H), 2.66 (s, 1H), 2.34 (s, 6H), 0.84 (d, J = 14.2Hz, 6H). 821 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.27 (d, J =8.3 Hz, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.91 (s, 1H), 7.81 (d, J = 2.5Hz, 1H), 7.73 (dd, J = 7.4, 1.2 Hz, 1H), 7.58-7.51 (m, 1H), 7.48 (d, J =6.3 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.71 (s, 1H), 5.92 (t, J = 54.8Hz, 1H), 4.13 (s, 4H), 3.89 (d, J = 14.7 Hz, 1H), 1.49 (d, J = 3.5 Hz,4H), 0.87 (d, J = 12.6 Hz, 6H). 822 1H NMR (400 MHz, Methanol-d4) δ 8.91(s, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.05 (d,J = 2.1 Hz, 1H), 8.02 (d, J = 2.0 Hz, 0H), 7.96 (s, 1H), 7.96-7.91 (m,1H), 7.80 (d, J = 2.6 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 6.31 (s, 1H),3.90 (d, J = 14.0 Hz, 1H), 3.57 (d, J = 14.0 Hz, 1H), 1.78 (s, 2H), 1.68(s, 2H), 0.83 (s, 10H). 823 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s,1H), 8.26 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H), 7.86 (s, 1H),7.82 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 7.4 Hz, 1H), 7.54 (t, J = 7.8 Hz,1H), 7.49 (d, J = 6.3 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.69 (s, 1H),4.12 (s, 3H), 3.81 (d, J = 13.7 Hz, 1H), 3.50 (d, J = 13.7 Hz, 1H), 1.49(ddd, J = 13.2, 8.4, 5.0 Hz, 1H), 1.25-1.14 (m, 2H), 1.02-0.94 (m, 2H),0.66 (s, 9H), 0.52-0.42 (m, 2H), 0.28 (q, J = 5.3 Hz, 2H). 824 1H NMR(400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.98(d, J = 6.2 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.77 (d, J= 7.3 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 6.3 Hz, 1H), 7.02(d, J = 2.4 Hz, 1H), 6.72 (s, 1H), 5.03-4.90 (m, 1H), 4.71 (d, J = 5.4Hz, 1H), 4.59 (d, J = 5.4 Hz, 1H), 4.12 (s, 3H), 3.81 (d, J = 13.7 Hz,1H), 3.51 (d, J = 13.7 Hz, 1H), 1.51 (dd, J = 7.0, 1.3 Hz, 3H), 0.66 (s,9H), 0.09 (s, 1H). 825 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H),8.27 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.87 (s, 1H), 7.83(d, J = 2.4 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.58 (d, J = 7.1 Hz, 0H),7.54 (dd, J = 8.3, 7.3 Hz, 1H), 7.50 (d, J = 6.3 Hz, 1H), 7.03 (d, J =2.5 Hz, 1H), 6.75 (s, 1H), 5.29-5.14 (m, 1H), 4.98-4.86 (m, 2H),4.83-4.74 (m, 1H), 4.68 (s, 0H), 4.30 (s, 0H), 4.12 (s, 3H), 3.81 (d, J= 13.6 Hz, 1H), 3.51 (d, J = 13.7 Hz, 1H), 0.66 (s, 9H). 826 1H NMR (400MHz, Methanol-d4) δ 8.83 (d, J = 2.2 Hz, 1H), 8.33 (s, 1H), 8.29 (s,1H), 8.07 (dd, J = 8.1, 2.3 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.81 (d,J = 2.5 Hz, 1H), 7.21 (d, J = 2.6 Hz, 1H), 6.29 (s, 1H), 4.00 (d, J =14.0 Hz, 1H), 3.57 (d, J = 14.0 Hz, 1H), 1.80-1.72 (m, 2H), 1.69 (d, J =9.2 Hz, 2H), 0.90 (s, 9H). 827 1H NMR (400 MHz, Methanol-d4) δ 8.41 (s,1H), 7.96 (s, 1H), 7.82-7.71 (m, 2H), 7.04 (d, J = 2.5 Hz, 1H), 6.87(dd, J = 8.5, 2.7 Hz, 1H), 6.19 (s, 1H), 4.25 (d, J = 15.0 Hz, 1H), 4.08(d, J = 14.9 Hz, 1H), 2.50 (s, 3H), 1.64 (s, 9H), 1.10 (d, J = 1.9 Hz,6H). 828 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.1 Hz, 1H), 8.48(dd, J = 8.4, 2.2 Hz, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 7.86 (d, J = 8.4Hz, 1H), 7.76 (dd, J = 2.6, 1.2 Hz, 1H), 7.32 (d, J = 2.5 Hz, 1H), 6.37(s, 1H), 3.96-3.81 (m, 1H), 3.66 (d, J = 13.9 Hz, 1H), 2.75 (s, 3H),1.82-1.74 (m, 2H), 1.69 (d, J = 5.5 Hz, 2H), 1.07 (s, 2H), 0.94 (s, 9H).829 1H NMR (400 MHz, Methanol-d4) δ 8.37 (d, J = 8.3 Hz, 1H), 8.29 (d, J= 15.4 Hz, 2H), 7.76-7.64 (m, 2H), 7.20 (d, J = 2.5 Hz, 1H), 6.37 (s,1H), 5.95 (t, J = 54.5 Hz, 1H), 3.85 (d, J = 13.9 Hz, 1H), 3.68 (d, J =13.9 Hz, 1H), 2.76 (d, J = 12.5 Hz, 6H), 1.56 (d, J = 2.5 Hz, 4H), 0.92(s, 9H). 830 1H NMR (400 MHz, Methanol-d4) δ 8.32 (s, 1H), 8.26 (s, 1H),7.88 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.70 (d, J = 8.0 Hz,1H), 7.01 (d, J = 2.5 Hz, 1H), 6.29 (s, 1H), 3.89 (d, J = 13.8 Hz, 1H),3.57 (d, J = 13.8 Hz, 1H), 2.59 (s, 3H), 1.80-1.63 (m, 4H), 0.86 (s,9H). 831 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.04 (s, 1H),7.82-7.70 (m, 2H), 7.01 (d, J = 2.5 Hz, 1H), 6.86 (dd, J = 8.5, 2.7 Hz,1H), 6.20 (s, 1H), 5.95 (t, J = 54.8 Hz, 1H), 4.42 (d, J = 14.9 Hz, 1H),4.15 (d, J = 14.9 Hz, 1H), 2.49 (s, 3H), 2.41-2.20 (m, 2H), 2.15-1.79(m, 3H), 1.53 (s, 5H). 832 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H),8.05 (s, 1H), 7.85-7.68 (m, 2H), 7.05 (d, J = 2.5 Hz, 1H), 6.86 (dd, J =8.5, 2.7 Hz, 1H), 6.22 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 5.48 (s, 1H),4.22 (d, J = 14.9 Hz, 1H), 4.06 (d, J = 14.9 Hz, 1H), 2.50 (s, 3H), 1.52(t, J = 1.7 Hz, 4H), 1.10 (d, J = 2.5 Hz, 6H). 833 1H NMR (400 MHz,Methanol-d4) δ 8.37 (s, 1H), 7.90 (s, 1H), 7.82-7.68 (m, 2H), 7.02 (d, J= 2.5 Hz, 1H), 6.86 (dd, J = 8.6, 2.7 Hz, 1H), 6.18 (s, 1H), 4.25-4.00(m, 2H), 2.68 (s, 1H), 2.51 (s, 3H), 2.37 (s, 6H), 1.09 (d, J = 3.3 Hz,6H). 834 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 7.97 (s, 1H),7.84-7.68 (m, 2H), 7.07 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz,1H), 6.20 (s, 1H), 5.98 (tt, J = 56.8, 3.4 Hz, 1H), 4.17 (dt, J = 8.2,4.0 Hz, 1H), 3.85 (d, J = 13.7 Hz, 1H), 3.69 (d, J = 13.8 Hz, 1H), 2.52(s, 3H), 2.26 (ddq, J = 10.8, 7.4, 3.8 Hz, 1H), 1.66 (q, J = 10.4, 8.7Hz, 1H), 1.52-1.43 (m, 1H), 0.89 (s, 9H). 835 1H NMR (400 MHz,Methanol-d4) δ 8.34 (s, 1H), 7.90 (s, 1H), 7.83-7.73 (m, 2H), 7.10 (d, J= 2.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.25 (s, 1H), 3.88 (d, J= 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.65 (t, J =18.7 Hz, 3H), 0.89 (s, 9H). 836 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s,1H), 7.90 (s, 1H), 7.83-7.73 (m, 2H), 7.10 (d, J = 2.5 Hz, 1H), 6.88(dd, J = 8.5, 2.7 Hz, 1H), 6.25 (s, 1H), 3.88 (d, J = 13.8 Hz, 1H), 3.65(d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.65 (t, J = 18.7 Hz, 3H), 0.89 (s,9H). 837 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 7.90 (s, 1H),7.84-7.75 (m, 2H), 7.18-7.08 (m, 1H), 6.88 (dd, J = 8.4, 2.8 Hz, 1H),6.25 (s, 1H), 3.90 (d, J = 13.8 Hz, 1H), 3.68 (d, J = 13.9 Hz, 1H), 2.50(s, 3H), 2.01-1.77 (m, 2H), 1.05 (t, J = 7.5 Hz, 3H), 0.89 (s, 9H). 8381H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 8.09(s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.69-7.58 (m, 1H), 7.58-7.37 (m, 4H),7.24 (s, 1H), 6.72 (d, J = 7.7 Hz, 1H), 6.60 (d, J = 7.4 Hz, 1H), 6.08(t, J = 54.1 Hz, 1H), 4.07 (dd, J = 14.7, 7.6 Hz, 1H), 3.86 (dd, J =14.6, 6.1 Hz, 1H), 3.48 (s, 3H), 1.45 (t, J = 4.4 Hz, 4H), 0.88 (d, J =18.4 Hz, 6H). 839 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 7.92 (s,1H), 7.86-7.67 (m, 2H), 7.13 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.4, 2.7Hz, 1H), 6.24 (s, 1H), 4.64 (d, J = 1.1 Hz, 2H), 3.86 (d, J = 13.8 Hz,1H), 3.72 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H), 1.13 (s, 4H), 0.90 (s,9H). 840 1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.88 (s, 1H),7.82-7.68 (m, 2H), 7.11 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz,1H), 6.22 (s, 1H), 5.59 (t, J = 56.0 Hz, 1H), 4.55 (s, 2H), 3.86 (d, J =13.8 Hz, 1H), 3.71 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H), 0.90 (s, 14H).841 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.04 (s, 1H),7.85-7.70 (m, 2H), 7.04 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz,1H), 6.21 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 4.21 (d, J = 14.9 Hz, 1H),4.05 (d, J = 14.9 Hz, 1H), 2.51 (s, 3H), 1.53 (t, J = 2.3 Hz, 4H), 1.10(d, J = 2.4 Hz, 6H). 842 1H NMR (400 MHz, Methanol-d4) δ 8.33 (d, J =6.9 Hz, 2H), 7.94 (s, 1H), 7.85-7.64 (m, 2H), 7.49 (t, J = 7.8 Hz, 1H),7.23 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.83 (d, J = 7.5 Hz,1H), 6.58 (s, 1H), 5.93 (t, J = 54.7 Hz, 1H), 4.15 (d, J = 14.7 Hz, 1H),3.91 (d, J = 14.8 Hz, 1H), 1.50 (s, 4H), 0.94 (d, J = 11.1 Hz, 6H). 8431H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.19 (s, 1H), 7.87-7.66(m, 2H), 7.04 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.23(s, 1H), 4.19 (d, J = 14.9 Hz, 1H), 4.04 (d, J = 14.9 Hz, 1H), 2.51 (s,3H), 1.81-1.59 (m, 4H), 1.09 (d, J = 1.9 Hz, 6H). 844 1H NMR (400 MHz,Methanol-d4) δ 8.35 (s, 1H), 8.21 (s, 1H), 7.79 (d, J = 2.5 Hz, 1H),7.66 (dt, J = 6.5, 2.1 Hz, 2H), 7.25 (d, J = 2.5 Hz, 1H), 6.38 (t, J =6.9 Hz, 1H), 6.18 (s, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.64 (d, J = 13.9Hz, 1H), 3.59 (s, 3H), 1.81-1.54 (m, 4H), 0.96 (s, 9H). 845 1H NMR (400MHz, Methanol-d4) δ 8.41 (s, 1H), 8.06 (s, 1H), 7.84-7.66 (m, 2H), 7.23(d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.27 (s, 1H), 5.94(t, J = 54.7 Hz, 1H), 3.99 (dd, J = 14.4, 7.2 Hz, 1H), 3.86 (dd, J =14.4, 7.4 Hz, 1H), 2.50 (s, 3H), 1.53 (s, 4H), 1.09 (d, J = 3.9 Hz, 6H),1.00 (d, J = 1.7 Hz, 6H), 0.73 (d, J = 7.3 Hz, 1H). 846 1H NMR (400 MHz,Methanol-d4) δ 8.37 (s, 1H), 7.96 (s, 1H), 7.83-7.65 (m, 2H), 7.01 (d, J= 2.5 Hz, 1H), 6.86 (dd, J = 8.4, 2.8 Hz, 1H), 6.16 (s, 1H), 4.20 (d, J= 14.9 Hz, 1H), 4.07 (d, J = 14.9 Hz, 1H), 2.50 (s, 3H), 1.65 (s, 3H),1.41-1.24 (m, 2H), 1.07 (dd, J = 17.4, 1.8 Hz, 8H). 847 1H NMR (400 MHz,Methanol-d4) δ 8.30 (s, 1H), 7.88-7.64 (m, 2H), 7.35 (dt, J = 7.5, 3.7Hz, 1H), 7.27-6.97 (m, 4H), 6.57 (dd, J = 3.2, 0.9 Hz, 1H), 6.38 (s,1H), 5.90 (t, J = 54.8 Hz, 1H), 5.48 (s, 1H), 3.96-3.69 (m, 4H), 3.53(d, J = 13.5 Hz, 1H), 1.61-1.32 (m, 4H), 0.79 (s, 9H). 848 1H NMR (400MHz, Methanol-d4) δ 8.36 (s, 1H), 8.20 (s, 1H), 7.81-7.72 (m, 2H), 7.22(d, J = 2.5 Hz, 1H), 6.89 (dd, J = 8.5, 2.8 Hz, 1H), 6.26 (s, 1H),4.04-3.91 (m, 2H), 2.52 (s, 3H), 2.49 (s, 1H), 1.74 (m, 8H), 1.69 (d, J= 8.0 Hz, 2H). 849 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.06(s, 1H), 7.83-7.71 (m, 2H), 7.22 (d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.5,2.8 Hz, 1H), 6.25 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 3.97 (m, 2H), 2.52(s, 3H), 2.49 (s, 1H), 1.74 (s, 6H), 1.53 (s, 4H). 850 1H NMR (400 MHz,Methanol-d4) δ 8.38 (d, J = 0.8 Hz, 1H), 8.00 (s, 1H), 7.85-7.77 (m,2H), 7.10 (d, J = 2.5 Hz, 1H), 6.89 (dd, J = 8.4, 2.7 Hz, 1H), 6.22 (s,1H), 3.90 (d, J = 13.8 Hz, 1H), 3.71 (d, J = 13.9 Hz, 1H), 2.52 (s, 3H),1.58 (s, 3H), 1.57 (s, 3H), 1.43-1.31 (m, 1H), 0.91 (s, 9H), 0.58-0.48(m, 2H), 0.47-0.37 (m, 2H). 851 1H NMR (400 MHz, Methanol-d4) δ 8.38 (s,1H), 7.91 (s, 1H), 7.83-7.75 (m, 2H), 7.11 (d, J = 2.5 Hz, 1H), 6.89(dd, J = 8.5, 2.8 Hz, 1H), 6.22 (s, 1H), 3.88 (d, J = 13.9 Hz, 1H), 3.73(d, J = 13.9 Hz, 1H), 2.52 (s, 3H), 1.66 (p, J = 6.9 Hz, 1H), 1.28-1.16(m, 2H), 1.17-1.04 (m, 2H), 0.97-0.85 (m, 15H). 852 1H NMR (400 MHz,Methanol-d4) δ 8.36 (s, 1H), 8.07 (s, 1H), 7.85-7.75 (m, 2H), 7.12-7.06(m, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.24 (s, 1H), 5.10 (t, J = 6.5Hz, 2H), 4.75 (dd, J = 6.9, 2.0 Hz, 2H), 3.86 (d, J = 13.8 Hz, 1H), 3.70(d, J = 13.8 Hz, 1H), 2.52 (s, 3H), 1.92 (s, 3H), 0.89 (s, 9H). 853 1HNMR (400 MHz, Methanol-d4) δ 8.37-8.29 (m, 2H), 7.95 (s, 1H), 7.81-7.73(m, 2H), 7.53-7.38 (m, 2H), 6.99 (d, J = 2.5 Hz, 1H), 6.87 (d, J = 7.5Hz, 1H), 6.58 (s, 1H), 5.07 (dd, J = 6.9, 3.0 Hz, 2H), 4.72 (d, J = 6.9Hz, 2H), 3.80 (d, J = 13.6 Hz, 1H), 3.61 (s, 3H), 3.52 (d, J = 13.6 Hz,1H), 1.89 (s, 3H), 0.72 (s, 9H). 854 1H NMR (400 MHz, Methanol-d4) δ8.36 (d, J = 1.4 Hz, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.79 (d, J = 2.4 Hz,1H), 7.10 (d, J = 2.4 Hz, 1H), 6.92-6.85 (m, 1H), 6.22 (s, 1H),4.81-4.55 (m, 3H), 3.92 (d, J = 13.9 Hz, 1H), 3.63 (d, J = 13.8 Hz, 1H),2.50 (s, 3H), 1.58 (d, 3H), 0.89 (s, 9H). 855 1H NMR (400 MHz,Methanol-d4) δ 9.59 (s, 1H), 8.59 (d, J = 6.4 Hz, 1H), 8.47 (s, 1H),8.34 (s, 1H), 8.33-8.30 (m, 2H), 7.79 (d, J = 2.5 Hz, 1H), 7.30 (d, J =2.5 Hz, 1H), 6.66 (s, 1H), 3.83 (d, J = 13.9 Hz, 1H), 3.61 (d, J = 13.9Hz, 1H), 1.81-1.72 (m, 2H), 1.72-1.61 (m, 2H), 0.82 (s, 9H). 856 1H NMR(400 MHz, Methanol-d4) δ 9.59 (s, 1H), 8.58 (d, J = 6.4 Hz, 1H), 8.46(s, 1H), 8.33-8.27 (m, 2H), 8.06 (s, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.27(d, J = 2.6 Hz, 1H), 6.59 (d, J = 1.0 Hz, 1H), 3.97-3.87 (m, 1H), 3.82(d, J = 13.8 Hz, 1H), 3.62 (d, J = 13.9 Hz, 1H), 1.29-1.12 (m, 4H), 0.81(s, 9H). 857 1H NMR (400 MHz, Methanol-d4) δ 8.39 (s, 1H), 7.82 (t, J =8.1 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.83(dd, J = 8.5, 2.6 Hz, 1H), 6.09 (s, 1H), 4.03 (d, J = 13.8 Hz, 1H), 3.84(tt, J = 7.4, 3.9 Hz, 1H), 3.51 (d, J = 13.8 Hz, 1H), 2.38 (s, 3H), 1.87(tt, J = 8.5, 5.4 Hz, 1H), 1.34-1.26 (m, 2H), 1.26-1.19 (m, 2H), 1.07(ddd, J = 8.5, 3.4, 1.6 Hz, 2H), 0.98-0.90 (m, 1H), 0.85 (s, 9H),0.83-0.76 (m, 1H). 858 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H),7.84 (t, J = 8.1 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.05 (d, J = 2.6 Hz,1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.19 (s, 1H), 4.89 (s, 1H),4.80-4.69 (m, 1H), 4.69-4.56 (m, 1H), 4.25 (d, J = 14.8 Hz, 1H), 3.99(d, J = 14.9 Hz, 1H), 2.50 (s, 3H), 1.61-1.54 (m, 3H), 1.10 (s, 3H),1.09 (s, 3H). 859 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 7.88 (t,J = 8.1 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H),6.86 (dd, J = 8.5, 2.7 Hz, 1H), 6.13 (s, 1H), 3.97 (d, J = 13.8 Hz, 1H),3.93 (s, 3H), 3.68-3.61 (m, 1H), 3.53 (d, J = 13.8 Hz, 1H), 2.45 (s,3H), 1.29-1.21 (m, 2H), 1.21-1.13 (m, 2H), 0.87 (s, 9H). 860 1H NMR (400MHz, Methanol-d4) δ 8.36 (s, 1H), 7.90 (s, 1H), 7.83-7.70 (m, 2H), 7.10(d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.21 (s, 1H), 3.85(d, J = 13.9 Hz, 1H), 3.71 (d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 1.32-1.22(m, 2H), 1.12-1.02 (m, 2H), 0.90 (s, 9H), 0.88 (s, 9H). 861 1H NMR (400MHz, Methanol-d4) δ 8.38 (s, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.77 (d, J =2.5 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H),6.16 (s, 1H), 4.23 (d, J = 14.9 Hz, 1H), 4.03 (d, J = 14.9 Hz, 1H), 2.72(s, 1H), 2.51 (s, 3H), 2.43 (s, 6H), 1.11 (s, 3H), 1.10 (s, 3H). 862 1HNMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H),7.78 (d, J = 2.5 Hz, 1H), 7.03 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5,2.7 Hz, 1H), 6.16 (s, 1H), 4.28 (d, J = 14.9 Hz, 1H), 3.97 (d, J = 14.9Hz, 1H), 2.49 (s, 3H), 1.54-1.44 (m, 1H), 1.28-1.18 (m, 2H), 1.10 (s,4H), 1.10-1.05 (m, 5H), 0.57-0.45 (m, 2H), 0.36-0.25 (m, 2H). 863 1H NMR(400 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7.76(d, J = 2.5 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.3, 2.7Hz, 1H), 6.15 (s, 1H), 4.26 (d, J = 14.9 Hz, 1H), 3.97 (d, J = 14.9 Hz,1H), 2.49 (s, 3H), 1.60 (s, 3H), 1.41-1.28 (m, 2H), 1.14-1.05 (m, 6H).864 1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.85 (t, J = 8.1 Hz,1H), 7.76 (d, J = 2.5 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.87 (dd, J =8.5, 2.7 Hz, 1H), 6.15 (s, 1H), 4.23 (d, J = 14.8 Hz, 1H), 4.00 (d, J =14.9 Hz, 1H), 3.72-3.58 (m, 1H), 2.51 (s, 3H), 1.31-1.15 (m, 3H), 1.10(s, 3H), 1.09 (s, 3H). 865 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H),7.88 (t, J = 8.1 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.08 (d, J = 2.6 Hz,1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.19 (s, 1H), 3.90 (d, J = 13.8 Hz,1H), 3.61 (d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 1.54-1.42 (m, 1H),1.27-1.22 (m, 2H), 1.10-1.05 (m, 2H), 0.89 (s, 9H), 0.52-0.47 (m, 2H),0.34-0.28 (m, 2H). 866 1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H),7.87 (s, 1H), 7.84-7.76 (m, 2H), 7.10 (d, J = 2.5 Hz, 1H), 6.88 (dd, J =8.5, 2.8 Hz, 1H), 6.23 (s, 1H), 4.23 (m, 2H), 3.86 (s, 1H), 3.68 (d, J =13.8 Hz, 1H), 2.51 (s, 3H), 0.96 (s, 3H), 0.90 (s, 9H), 0.68 (s, 2H),0.43 (s, 2H). 867 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.00 (s,1H), 7.83-7.72 (m, 2H), 7.02 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.4, 2.7Hz, 1H), 6.18 (s, 1H), 4.22 (d, J = 14.9 Hz, 1H), 4.03 (d, J = 14.9 Hz,1H), 2.50 (s, 3H), 1.62-1.47 (m, 1H), 1.32-1.17 (m, 2H), 1.10 (s, 3H),1.09 (s, 3H), 1.06-0.97 (m, 2H), 0.58-0.46 (m, 2H), 0.38-0.28 (m, 2H).868 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 7.87 (t, J = 8.1 Hz,1H), 7.77 (d, J = 2.5 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.86 (dd, J =8.4, 2.7 Hz, 1H), 6.14 (s, 1H), 3.96 (d, J = 13.8 Hz, 1H), 3.91 (s, 3H),3.51 (d, J = 13.8 Hz, 1H), 2.69 (s, 1H), 2.44 (s, 3H), 2.43 (s, 6H),0.86 (s, 9H). 869 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.02 (s,1H), 7.85-7.74 (m, 2H), 7.11 (d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.8Hz, 1H), 6.26 (s, 1H), 5.37-5.17 (m, 1H), 5.05-4.90 (m, 2H), 4.84 (m,2H), 3.89 (d, J = 13.8 Hz, 1H), 3.69 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H),0.89 (s, 9H). 870 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 8.34 (d,1H), 7.94 (s, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H),7.50 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 2.5 Hz,1H), 6.86 (d, J = 7.8 Hz, 1H), 6.60 (s, 1H), 6.25 (tt, J = 56.0, 4.1 Hz,1H), 5.92 (t, J = 54.7 Hz, 1H), 4.58-4.30 (m, 2H), 3.85 (d, J = 13.7 Hz,1H), 3.52 (d, J = 13.7 Hz, 1H), 1.53-1.47 (m, 4H), 0.73 (s, 9H). 871 1HNMR (400 MHz, Methanol-d4) δ 8.34 (d, J = 8.2 Hz, 1H), 8.30 (s, 1H),7.92 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.48(t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H),6.87 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 5.92 (t, J = 54.8 Hz, 1H), 3.79(d, J = 13.6 Hz, 1H), 3.61 (s, 3H), 3.50 (d, J = 13.6 Hz, 1H), 1.50 (s,4H), 0.72 (s, 9H). 872 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H),7.84 (s, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.06(d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.6, 2.7 Hz, 1H), 6.19 (s, 1H), 4.17(dd, J = 7.0, 3.4 Hz, 1H), 3.84 (d, J = 14.0 Hz, 1H), 3.68 (d, J = 14.0Hz, 1H), 2.51 (s, 3H), 1.70 (q, J = 6.0 Hz, 2H), 1.20-1.09 (m, 1H),1.06-0.90 (m, 2H), 0.88 (s, 9H), 0.87-0.76 (m, 1H). 873 1H NMR (400 MHz,Methanol-d4) δ 8.31 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 7.98 (s, 1H),7.81 (d, J = 2.5 Hz, 1H), 7.43 (d, J = 3.6 Hz, 1H), 7.31 (d, J = 5.2 Hz,1H), 7.12 (d, J = 2.5 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 6.51 (s, 1H),5.92 (t, J = 54.7 Hz, 1H), 3.90 (d, J = 13.7 Hz, 1H), 3.88 (s, 3H), 3.45(d, J = 13.7 Hz, 1H), 1.50 (hr s, 4H), 0.76 (s, 9H). 874 1H NMR (400MHz, Methanol-d4) δ 8.34 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H), 8.09 (s,1H), 7.81 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.51 (t, J =7.8 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 2.6 Hz, 1H), 6.85(d, J = 7.9 Hz, 1H), 6.62 (s, 1H), 6.42-6.06 (m, 1H), 4.55-4.33 (m, 2H),3.85 (d, J = 13.7 Hz, 1H), 3.53 (d, J = 13.6 Hz, 1H), 1.75-1.59 (m, 4H),0.73 (s, 9H). 875 1H NMR (400 MHz, Methanol-d4) δ 8.35 (d, J = 8.0 Hz,1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.78 (d, J =7.5 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.03(d, J = 2.5 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.62 (s, 1H), 5.02-4.91(m, 1H), 4.81-4.65 (m, 1H), 3.85 (d, J = 13.7 Hz, 1H), 3.50 (d, J = 13.8Hz, 1H), 1.78-1.61 (m, 4H), 0.71 (s, 9H). 876 1H NMR (400 MHz,Methanol-d4) δ 8.32 (d, J = 7.8 Hz, 1H), 8.32 (s, 1H), 7.92 (s, 1H),7.80 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 7.8 Hz,1H), 7.22 (d, J = 7.5 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.85 (d, J =7.6 Hz, 1H), 6.59 (s, 1H), 5.93 (t, J = 54.7 Hz, 1H), 3.81 (d, J = 13.6Hz, 1H), 3.51 (d, J = 13.6 Hz, 1H), 1.50 (s, 4H), 0.73 (s, 9H). 877 1HNMR (400 MHz, Methanol-d4) δ 8.34 (d, J = 8.1 Hz, 1H), 8.31 (s, 1H),7.82 (s, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.49(t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H),6.86 (d, J = 7.8 Hz, 1H), 6.58 (s, 1H), 5.05-4.91 (m, 1H), 4.67 (d, J =46.9 Hz, 1H), 4.66 (d, J = 46.9 Hz, 1H), 3.82 (d, J = 13.6 Hz, 1H), 3.61(s, 3H), 3.50 (d, J = 13.6 Hz, 1H), 1.56-1.49 (m, 3H), 0.71 (s, 9H). 8781H NMR (400 MHz, Methanol-d4) δ 8.36-8.30 (m, 2H), 7.89 (s, 1H), 7.80(d, J = 2.4 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H),7.42 (d, J = 7.7 Hz, 1H), 6.99 (s, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.57(s, 1H), 4.59 (d, J = 48.6 Hz, 2H), 3.84 (d, J = 13.6 Hz, 1H), 3.61 (s,3H), 3.52 (d, J = 13.6 Hz, 1H), 1.53-1.26 (m, 4H), 0.72 (s, 9H). 879 1HNMR (400 MHz, Methanol-d4) δ 8.36-8.29 (m, 2H), 7.85 (s, 1H), 7.78 (d, J= 2.4 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42(d, J = 7.6 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H),6.54 (s, 1H), 3.81 (d, J = 13.7 Hz, 1H), 3.61 (d, J = 1.2 Hz, 3H), 3.51(d, J = 13.7 Hz, 1H), 1.63 (s, 3H), 1.36-1.22 (m, 2H), 1.09-0.96 (m,2H), 0.71 (s, 9H). 880 1H NMR (400 MHz, Methanol-d4) δ 8.37-8.30 (m,2H), 7.89 (s, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H),7.49 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 2.4 Hz,1H), 6.86 (d, J = 7.7 Hz, 1H), 6.61 (s, 1H), 5.26-5.21 (m, 1H),5.03-4.92 (m, 2H), 4.86-4.76 (m, 2H), 3.86 (d, J = 13.6 Hz, 1H), 3.61(s, 3H), 3.52 (d, J = 13.7 Hz, 1H), 0.72 (s, 9H). 881 1H NMR (400 MHz,Methanol-d4) δ 8.07-8.00 (m, 2H), 7.60 (s, 1H), 7.51 (d, J = 2.4 Hz,1H), 7.45 (d, J = 7.5 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.12 (d, J =7.6 Hz, 1H), 6.70 (s, 1H), 6.56 (d, J = 7.8 Hz, 1H), 6.26 (s, 1H), 3.56(d, J = 13.5 Hz, 1H), 3.31 (d, J = 1.3 Hz, 3H), 3.23 (d, J = 13.6 Hz,1H), 1.25-1.16 (m, 1H), 0.95-0.83 (m, 2H), 0.75-0.65 (m, 2H), 0.43 (s,9H), 0.24-0.14 (m, 2H), 0.05-−0.06 (m, 2H). 882 1H NMR (400 MHz,Methanol-d4) δ 8.05 (d, J = 8.1 Hz, 2H), 7.61 (s, 1H), 7.51 (d, J = 2.4Hz, 1H), 7.47-7.40 (m, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.7Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 6.25 (s,1H), 3.89 (d, J = 14.7 Hz, 1H), 3.64 (d, J = 14.7 Hz, 1H), 3.33 (s, 3H),1.30-1.16 (m, 1H), 0.96-0.88 (m, 2H), 0.75-0.68 (m, 2H), 0.69 (s, 3H),0.64 (s, 3H), 0.21 (ddd, J = 8.2, 6.1, 4.5 Hz, 2H), 0.08-−0.02 (m, 2H).883 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 8.34 (d, J = 8.2 Hz,1H), 7.79 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 7.1 Hz, 1H),7.48 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 2.5 Hz,1H), 6.84 (d, J = 7.5 Hz, 1H), 6.54 (s, 1H), 4.13 (d, J = 14.8 Hz, 1H),3.94 (d, J = 14.8 Hz, 1H), 3.61 (s, 3H), 2.67 (s, 1H), 2.35 (s, 6H),0.94 (d, J = 19.8 Hz, 6H). 884 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s,1H), 8.34 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H),7.70 (d, J = 6.8 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz,1H), 6.96 (d, J = 2.5 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 6.52 (s, 1H),4.15 (d, J = 14.7 Hz, 1H), 3.93 (d, J = 14.7 Hz, 1H), 3.61 (s, 3H), 1.63(s, 3H), 1.36-1.24 (m, 2H), 1.07-1.01 (m, 2H), 0.94 (d, J = 19.6 Hz,6H). 885 1H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.14 (s, 1H),8.11 (dd, J = 5.1, 1.9 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.69 (dd, J =7.3, 1.8 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 6.95 (dd, J = 7.4, 5.0 Hz,1H), 6.29 (s, 1H), 3.94 (d, J = 13.9 Hz, 1H), 3.94 (s, 3H), 3.74 (d, J =13.9 Hz, 1H), 1.83-1.57 (m, 4H), 0.94 (s, 9H). 886 1H NMR (400 MHz,Methanol-d4) δ 8.25 (d, J = 7.3 Hz, 2H), 7.98 (s, 1H), 7.69 (d, J = 2.5Hz, 1H), 7.64-7.57 (m, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 7.6Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 6.49 (s,1H), 4.05 (d, J = 14.7 Hz, 1H), 3.85 (d, J = 14.7 Hz, 1H), 3.52 (s, 3H),1.73-1.49 (m, 4H), 0.88 (s, 3H), 0.84 (s, 3H). 887 1H NMR (400 MHz,Methanol-d4) δ 8.23 (s, 1H), 8.12 (d, J = 9.9 Hz, 1H), 7.71 (s, 1H),7.70 (d, J = 2.5 Hz, 1H), 7.55-7.49 (m, 2H), 7.30 (q, J = 4.8 Hz, 1H),6.89 (d, J = 2.5 Hz, 1H), 6.62 (d, J = 9.9 Hz, 1H), 6.57 (s, 1H), 3.79(d, J = 13.7 Hz, 1H), 3.68 (s, 3H), 3.37 (d, J = 13.7 Hz, 1H), 2.58 (s,1H), 2.26 (s, 6H), 0.61 (s, 9H). 888 1H NMR (400 MHz, Methanol-d4) δ8.23 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.71-7.68 (m, 2H), 7.66 (d, J =7.4 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.87(d, J = 2.5 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.47 (s, 1H), 3.72 (d, J= 13.6 Hz, 1H), 3.41 (d, J = 13.6 Hz, 1H), 2.58 (s, 1H), 2.26 (s, 6H),0.63 (s, 9H). 889 1H NMR (400 MHz, Methanol-d4) δ 8.39-8.33 (m, 1H),8.33 (s, 1H), 8.12 (s, 1H), 7.91 (t, J = 60.0 Hz, 1H), 7.87-7.79 (m,2H), 7.54 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.00 (d, J =2.5 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.62 (s, 1H), 3.86 (d, J = 13.7Hz, 1H), 3.50 (d, J = 13.7 Hz, 1H), 1.85-1.55 (m, 4H), 0.73 (s, 9H). 8901H NMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H), 8.12 (d, J = 9.9 Hz, 1H),8.00 (s, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.53 (d, J = 4.4 Hz, 2H), 7.30(t, J = 4.3 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.63 (d, J = 10.1 Hz,1H), 6.61 (s, 1H), 3.79 (d, J = 13.7 Hz, 1H), 3.68 (s, 3H), 3.37 (d, J =13.7 Hz, 1H), 1.74-1.45 (m, 4H), 0.62 (s, 9H). 891 1H NMR (400 MHz,Methanol-d4) δ 8.37-8.30 (m, 2H), 7.79 (d, J = 1.9 Hz, 2H), 7.76-7.67(m, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 6.97 (d, J= 2.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.56 (s, 1H), 3.82 (d, J = 13.6Hz, 1H), 3.61 (s, 3H), 3.52 (d, J = 13.7 Hz, 1H), 2.67 (s, 1H), 2.35 (d,J = 1.1 Hz, 6H), 0.71 (s, 9H). 892 1H NMR (400 MHz, Methanol-d4) δ9.09-8.97 (m, 2H), 8.29 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.97-7.88 (m,2H), 7.88-7.76 (m, 3H), 7.09 (d, J = 2.4 Hz, 1H), 6.90 (s, 1H), 4.72 (d,J = 5.5 Hz, 1H), 4.60 (d, J = 5.8 Hz, 1H), 3.78 (d, J = 13.8 Hz, 1H),3.46 (d, J = 13.8 Hz, 1H), 1.53 (d, J = 7.4 Hz, 3H), 0.65 (s, 9H). 8931H NMR (400 MHz, Methanol-d4) δ 9.12-9.04 (m, 2H), 8.29 (s, 1H), 8.14(d, J = 8.5 Hz, 1H), 8.03 (s, 1H), 8.00-7.91 (m, 1H), 7.87 (m, 2H), 7.80(d, J = 2.5 Hz, 1H), 7.11 (d, J = 2.5 Hz, 1H), 6.94 (s, 1H), 5.00-4.74(m, 4H), 3.80 (d, J = 13.8 Hz, 1H), 3.47 (d, J = 13.8 Hz, 1H), 0.66 (s,9H). 894 1H NMR (400 MHz, Acetonitrile-d3) δ 9.15-9.07 (m, 2H), 8.41 (s,1H), 8.30 (d, J = 8.2 Hz, 1H), 8.02-7.81 (m, 4H), 7.76 (d, J = 2.4 Hz,1H), 6.88 (d, J = 2.3 Hz, 1H), 6.81 (s, 1H), 6.25 (s, 1H), 5.90 (s, 2H),5.85 (t, J = 54.6 Hz, 1H), 4.09 (dd, J = 14.7, 7.4 Hz, 1H), 3.86 (dd, J= 14.7, 5.8 Hz, 1H), 1.51-1.43 (m, 4H), 0.94 (d, J = 21.8 Hz, 6H). 8951H NMR (400 MHz, Acetonitrile-d3) δ 9.13 (t, J = 7.7 Hz, 2H), 8.41 (s,1H), 8.30 (d, J = 8.1 Hz, 1H), 8.02-7.87 (m, 3H), 7.78-7.70 (m, 2H),6.85 (s, 1H), 6.77 (s, 1H), 5.88 (s, 1H), 4.10 (dd, J = 14.5, 7.2 Hz,1H), 3.91-3.81 (m, 1H), 1.60 (s, 3H), 1.25 (s, 2H), 1.01 (d, J = 1.9 Hz,4H), 0.93 (d, J = 22.7 Hz, 6H). 896 1H NMR (400 MHz, Acetonitrile-d3) δ9.11 (s, 1H), 9.01 (d, J = 8.6 Hz, 1H), 8.39 (s, 1H), 8.26 (d, J = 8.0Hz, 1H), 7.89 (s, 1H), 7.82 (d, J = 9.0 Hz, 2H), 7.74 (s, 1H), 6.85 (s,1H), 5.88 (s, 1H), 4.09 (dd, J = 14.6, 7.3 Hz, 1H), 3.85 (dd, J = 14.6,5.7 Hz, 1H), 3.01 (s, 1H), 2.87 (s, 1H), 2.01 (s, 1H), 1.16 (d, J = 4.5Hz, 2H), 0.95 (s, 5H), 0.90 (s, 3H), 0.47 (dd, J = 7.4, 5.7 Hz, 2H),0.26 (d, J = 5.4 Hz, 2H). 897 1H NMR (400 MHz, Acetonitrile-d3) δ 9.09(dd, J = 14.8, 6.8 Hz, 2H), 8.40 (s, 1H), 8.29 (d, J = 8.2 Hz, 1H),7.99-7.83 (m, 3H), 7.75 (d, J = 2.4 Hz, 1H), 7.65 (s, 1H), 6.87 (s, 1H),6.78 (s, 1H), 5.89 (s, 1H), 4.08 (dd, J = 14.7, 7.2 Hz, 1H), 3.87 (dd, J= 14.7, 5.8 Hz, 1H), 2.66 (s, 1H), 2.32 (s, 6H), 0.93 (d, J = 21.2 Hz,6H). 898 1H NMR (400 MHz, Acetonitrile-d3) δ 9.61 (s, 1H), 8.60 (d, J =6.7 Hz, 1H), 8.49 (d, J = 6.7 Hz, 1H), 8.38-8.33 (m, 2H), 8.19 (d, J =7.3 Hz, 1H), 7.92-7.86 (m, 1H), 7.86 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H),6.90 (d, J = 2.4 Hz, 1H), 6.81 (s, 1H), 6.06 (t, J = 55.5 Hz, 1H), 5.80(s, 1H), 3.68 (m, 1H), 3.47 (m, 1H), 1.70 (m, 6H), 0.68 (s, 9H). 899 1HNMR (400 MHz, Acetonitrile-d3) δ 9.13-9.06 (m, 2H), 8.37 (s, 1H), 8.28(d, J = 8.3 Hz, 1H), 8.00-7.89 (m, 2H), 7.87 (dd, J = 8.7, 5.1 Hz, 1H),7.74 (d, J = 2.4 Hz, 2H), 6.91 (d, J = 2.5 Hz, 1H), 6.82 (s, 1H), 5.79(s, 1H), 4.86 (ddd, J = 64.1, 8.9, 5.4 Hz, 1H), 3.78 (dt, J = 10.2, 5.4Hz, 1H), 3.68 (dd, J = 13.4, 6.6 Hz, 1H), 3.48 (dd, J = 13.4, 5.0 Hz,1H), 1.94-1.79 (m, 1H), 1.64-1.49 (m, 1H), 0.69 (s, 9H). 900 1H NMR (400MHz, Acetonitrile-d3) δ 9.16 (d, J = 8.9 Hz, 1H), 8.35 (d, J = 7.5 Hz,2H), 8.03-7.90 (m, 2H), 7.82 (d, J = 8.9 Hz, 1H), 7.75-7.69 (m, 2H),6.98 (d, J = 2.4 Hz, 1H), 6.81 (s, 1H), 6.26 (s, 1H), 6.00 (s, 1H), 3.70(dd, J = 13.5, 6.1 Hz, 1H), 3.52 (dd, J = 13.7, 4.6 Hz, 1H), 3.00 (s,4H), 2.67 (s, 1H), 2.33 (s, 6H), 0.72 (s, 9H). 901 1H NMR (400 MHz,Acetonitrile-d3) δ 9.06 (d, J = 4.8 Hz, 1H), 8.94 (d, J = 8.9 Hz, 1H),8.42 (s, 1H), 8.30-8.16 (m, 1H), 7.89-7.83 (m, 2H), 7.77 (dd, J = 8.7,4.7 Hz, 2H), 7.68-7.60 (m, 1H), 7.59 (s, 1H), 7.38 (t, J = 52.2 Hz, 1H),6.96 (s, 1H), 6.94-6.87 (m, 1H), 6.23 (s, 1H), 5.74 (s, 1H), 3.80-3.27(m, 2H), 2.31 (d, J = 6.4 Hz, 6H), 1.03 (s, 1H), 0.56 (s, 9H). 902 1HNMR (400 MHz, Acetonitrile-d3) δ 9.14-9.07 (m, 1H), 8.37 (s, 1H), 8.32(d, J = 8.4 Hz, 1H), 8.00-7.90 (m, 2H), 7.80 (d, J = 8.9 Hz, 1H), 7.76(s, 1H), 7.72 (d, J = 2.5 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.76 (s,1H), 6.20 (s, 1H), 5.83 (s, 1H), 3.70 (dd, J = 13.3, 7.0 Hz, 1H), 3.50(dd, J = 13.4, 5.3 Hz, 1H), 2.99 (s, 3H), 1.61 (s, 3H), 1.25 (s, 2H),1.06-0.99 (m, 2H), 0.72 (s, 9H). 903 1H NMR (400 MHz, Methanol-d4) δ8.89 (s, 1H), 8.37 (s, 1H), 8.07 (s, 1H), 7.76 (d, J = 2.5 Hz, 1H), 7.31(d, J = 2.5 Hz, 1H), 6.38 (s, 1H), 3.89 (d, J = 13.8 Hz, 1H), 3.75 (d, J= 13.9 Hz, 1H), 2.46 (s, 3H), 1.62-1.48 (m, 1H), 1.23 (m, 2H), 1.03 (m,2H), 0.96 (s, 9H), 0.53 (dd, J = 8.3, 1.8 Hz, 2H), 0.40-0.27 (m, 2H).904 1H NMR (400 MHz, Methanol-d4) δ 8.91 (s, 1H), 8.41 (s, 1H), 8.25 (s,1H), 7.79 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 6.44 (s, 1H),3.92 (d, J = 13.9 Hz, 1H), 3.77 (d, J = 13.9 Hz, 1H), 2.46 (s, 3H),1.82-1.63 (m, 4H), 0.96 (s, 9H). 905 1H NMR (400 MHz, Methanol-d4) δ8.30 (s, 1H), 8.23 (d, J = 2.5 Hz, 1H), 8.14 (s, 1H), 7.75 (m, 2H), 7.24(d, J = 2.5 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 6.10 (s, 1H), 4.01-3.84(m, 4H), 3.64 (d, J = 13.9 Hz, 1H), 1.79-1.59 (m, 4H), 0.93 (s, 9H). 9061H NMR (400 MHz, Methanol-d4) δ 8.27 (s, 1H), 7.88 (t, J = 8.1 Hz, 1H),7.73 (d, J = 2.5 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5,2.7 Hz, 1H), 6.18 (s, 1H), 3.95 (d, J = 1.2 Hz, 3H), 3.84 (d, J = 13.8Hz, 1H), 3.58 (d, J = 13.7 Hz, 1H), 2.52 (s, 3H), 0.87 (s, 9H). 907 1HNMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.20 (s, 1H), 7.85 (t, J =8.1 Hz, 1H), 7.76 (d, J = 2.5 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 6.88(dd, J = 8.5, 2.7 Hz, 1H), 6.24 (s, 1H), 3.92 (d, J = 13.8 Hz, 1H), 3.63(d, J = 13.8 Hz, 1H), 2.53 (s, 3H), 2.45 (s, 3H), 2.00 (d, J = 3.8 Hz,4H), 0.89 (s, 9H). 908 1H NMR (400 MHz, Methanol-d4) δ 8.32 (s, 1H),7.88 (t, J = 8.1 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.00 (d, J = 2.5 Hz,1H), 6.86 (dd, J = 8.6, 2.6 Hz, 1H), 6.15 (s, 1H), 4.04-3.83 (m, 7H),3.50 (d, J = 13.8 Hz, 1H), 2.45 (s, 3H), 0.86 (s, 9H). 909 1H NMR (400MHz, Methanol-d4) δ 9.40 (d, J = 0.9 Hz, 1H), 8.59 (s, 1H), 8.30 (s,1H), 8.21 (d, J = 8.7 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J = 7.3 Hz, 1H),7.85 (t, J = 7.8 Hz, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.04 (d, J = 2.5 Hz,1H), 6.86 (s, 1H), 3.79 (d, J = 13.7 Hz, 1H), 3.51-3.44 (m, 1H), 3.34(s, 2H), 1.77-1.59 (m, 4H), 0.65 (s, 9H). 910 1H NMR (400 MHz,Methanol-d4) δ 9.05 (dd, J = 4.2, 1.5 Hz, 1H), 8.67 (dd, J = 8.8, 1.6Hz, 1H), 8.31 (s, 1H), 8.21 (d, J = 7.5 Hz, 2H), 7.84-7.79 (m, 2H), 7.69(dd, J = 8.7, 4.2 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.92 (s, 1H), 3.81(d, J = 13.7 Hz, 1H), 3.37 (d, J = 13.7 Hz, 1H), 1.77-1.55 (m, 4H), 0.58(s, 10H). 911 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H), 8.23 (s,1H), 7.95 (s, 1H), 7.70 (s, 2H), 7.62 (s, 1H), 7.49 (s, 1H), 7.42 (s,1H), 6.80 (s, 1H), 6.66 (s, 1H), 4.08 (d, J = 5.0 Hz, 4H), 2.62 (s, 1H),2.30 (s, 8H), 0.67 (s, 9H). 912 1H NMR (400 MHz, Methanol-d4) δ 8.39 (d,J = 1.4 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 6.2 Hz, 1H),7.71 (d, J = 5.7 Hz, 2H), 7.60 (s, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.43(d, J = 6.3 Hz, 1H), 6.77 (s, 1H), 6.63 (s, 1H), 4.08 (t, J = 0.9 Hz,3H), 3.90 (d, J = 13.9 Hz, 1H), 3.57 (d, J = 13.8 Hz, 1H), 1.18-0.99 (m,5H), 0.66 (d, J = 1.0 Hz, 10H). 913 1H NMR (400 MHz, Methanol-d4) δ 8.39(d, J = 1.2 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.95 (dd, J = 6.2, 1.0Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.62-7.59(m, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 6.3 Hz, 1H), 6.76 (d, J= 2.3 Hz, 1H), 6.64 (s, 1H), 4.08 (d, J = 1.1 Hz, 3H), 3.90 (d, J = 13.5Hz, 1H), 3.57 (d, J = 13.8 Hz, 1H), 1.58 (d, J = 0.7 Hz, 3H), 1.28-1.19(m, 2H), 1.03-0.93 (m, 2H), 0.66 (d, J = 1.1 Hz, 9H). 914 1H NMR (400MHz, Methanol-d4) δ 8.41 (d, J = 1.9 Hz, 1H), 8.27-8.20 (m, 1H), 7.96(dd, J = 6.2, 1.8 Hz, 1H), 7.85 (s, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.62(dd, J = 2.6, 1.6 Hz, 1H), 7.54-7.46 (m, 1H), 7.43 (d, J = 6.3 Hz, 1H),6.82 (d, J = 2.2 Hz, 1H), 6.69 (s, 1H), 5.87 (t, J = 54.7 Hz, 1H), 4.09(d, J = 1.9 Hz, 3H), 3.92 (d, J = 14.2 Hz, 1H), 3.60 (d, J = 13.4 Hz,1H), 1.46 (s, 3H), 0.68 (d, J = 1.7 Hz, 10H). 915 1H NMR (400 MHz,Methanol-d4) δ 9.18 (s, 1H), 8.45 (s, 1H), 8.15 (s, 1H), 8.12 (s, 1H),8.03 (s, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H),7.70-7.61 (m, 2H), 6.90 (d, J = 2.3 Hz, 1H), 6.77 (s, 1H), 3.95 (d, J =13.8 Hz, 1H), 3.68 (d, J = 13.8 Hz, 1H), 1.78-1.56 (m, 4H), 0.73 (s,9H). 916 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1H), 8.41 (d, J = 8.5Hz, 1H), 8.27 (d, J = 6.0 Hz, 1H), 8.11 (s, 1H), 7.96 (d, J = 6.1 Hz,1H), 7.94-7.88 (m, 1H), 7.74 (dd, J = 8.5, 7.3 Hz, 1H), 7.68 (d, J = 2.2Hz, 1H), 6.83 (d, J = 2.9 Hz, 2H), 3.99 (d, J = 13.8 Hz, 1H), 3.56 (d, J= 13.8 Hz, 1H), 3.34 (s, 1H), 1.77-1.54 (m, 4H), 0.67 (s, 10H). 918 1HNMR (400 MHz, Methanol-d4) δ 8.94 (d, J = 4.4 Hz, 1H), 8.59 (d, J = 8.7Hz, 1H), 8.51 (s, 1H), 7.97 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.68-7.64(m, 1H), 7.59 (dd, J = 8.2, 4.9 Hz, 1H), 7.51-7.42 (m, 1H), 6.87 (d, J =2.3 Hz, 1H), 6.77 (s, 1H), 5.91 (t, J = 54.7 Hz, 1H), 4.32 (d, J = 14.9Hz, 1H), 3.99 (d, J = 14.9 Hz, 1H), 1.49 (s, 3H), 0.95 (s, 3H), 0.92 (s,3H). 919 1H NMR (400 MHz, Methanol-d4) δ 8.94 (d, J = 4.2 Hz, 1H), 8.59(d, J = 8.8 Hz, 1H), 8.49 (s, 1H), 7.88 (s, 1H), 7.69-7.63 (m, 2H), 7.59(dd, J = 8.2, 4.9 Hz, 1H), 7.49-7.42 (m, 1H), 6.82 (d, J = 2.3 Hz, 1H),6.72 (s, 1H), 4.32 (d, J = 14.9 Hz, 1H), 3.97 (d, J = 14.9 Hz, 1H), 1.61(s, 3H), 1.32-1.23 (m, 2H), 1.03 (s, 2H), 0.93 (s, 3H), 0.90 (s, 3H).920 1H NMR (400 MHz, Methanol-d4) δ 8.94 (d, J = 4.2 Hz, 1H), 8.59 (d, J= 8.8 Hz, 1H), 8.49 (s, 1H), 7.82 (s, 1H), 7.67 (d, J = 2.5 Hz, 1H),7.65 (d, J = 4.4 Hz, 1H), 7.61 (dd, J = 8.2, 4.9 Hz, 1H), 7.52-7.40 (m,1H), 6.87 (s, 1H), 6.76 (s, 1H), 4.01 (d, J = 13.9 Hz, 1H), 3.61 (d, J =13.9 Hz, 1H), 2.66 (s, 1H), 2.33 (s, 6H), 0.68 (s, 9H). 921 1H NMR (400MHz, Methanol-d4) δ 8.99 (dd, J = 4.3, 1.5 Hz, 1H), 8.60 (dd, J = 8.7,1.5 Hz, 1H), 8.50 (s, 1H), 8.12 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.70(d, J = 2.3 Hz, 1H), 7.66 (dd, J = 8.7, 4.3 Hz, 1H), 7.61 (d, J = 7.9Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.83 (s, 1H), 4.03 (d, J = 13.8 Hz,1H), 3.58 (d, J = 13.9 Hz, 1H), 1.76-1.55 (m, 4H), 0.67 (s, 9H). 922 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H),8.01 (d, J = 6.2 Hz, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.67 (d, J = 2.3 Hz,1H), 7.54 (dd, J = 8.3, 7.4 Hz, 1H), 7.45 (d, J = 6.2 Hz, 1H), 6.91 (d,J = 2.3 Hz, 1H), 6.75 (s, 1H), 4.12 (s, 3H), 3.97 (d, J = 13.8 Hz, 1H),3.65 (d, J = 13.8 Hz, 1H), 1.83-1.62 (m, 5H), 0.72 (s, 10H). 923 1H NMR(400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.01(d, J = 6.2 Hz, 1H), 7.80 (d, J = 7.1 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H),7.54 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 6.3 Hz, 1H), 6.91 (d, J = 2.3 Hz,1H), 6.73 (s, 1H), 5.85 (t, J = 54.2 Hz, 1H), 4.12 (s, 3H), 3.98 (d, J =13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 1.61-1.47 (m, 4H), 0.73 (s,8H), 0.70 (s, 1H). 924 1H NMR (400 MHz, Methanol-d4) δ 8.25 (d, J = 8.4Hz, 1H), 8.18 (s, 1H), 7.96 (d, J = 6.3 Hz, 1H), 7.85 (d, J = 7.3 Hz,1H), 7.56 (s, 0H), 7.53 (q, J = 2.8 Hz, 2H), 7.38 (d, J = 6.3 Hz, 1H),6.63 (s, 1H), 6.58 (s, 1H), 4.11 (s, 3H), 3.70 (d, J = 13.5 Hz, 1H),3.38 (d, J = 13.5 Hz, 1H), 2.98 (s, 1H), 2.85 (d, J = 0.8 Hz, 1H), 1.89(s, 2H), 1.74 (s, 2H), 1.28 (s, 1H), 0.96-0.84 (m, 0H), 0.61 (s, 9H).925 1H NMR (400 MHz, Methanol-d4) δ 8.25 (d, J = 8.3 Hz, 1H), 8.19 (s,1H), 7.96 (d, J = 6.2 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.58-7.48 (m,2H), 7.39 (d, J = 6.2 Hz, 1H), 6.62 (s, 1H), 6.57 (s, 1H), 5.99 (t, J =55.0 Hz, 1H), 4.11 (s, 3H), 3.71 (d, J = 13.4 Hz, 1H), 3.38 (d, J = 13.4Hz, 1H), 1.68 (s, 2H), 1.58 (s, 2H), 1.28 (s, 1H), 0.62 (s, 9H). 926 1HNMR (400 MHz, Methanol-d4) δ 8.29 (s, 1H), 8.01 (d, J = 8.3 Hz, 1H),7.72 (d, J = 6.2 Hz, 1H), 7.60 (s, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.42(d, J = 2.2 Hz, 1H), 7.30-7.24 (m, 1H), 7.17 (d, J = 6.3 Hz, 1H), 6.60(d, J = 2.3 Hz, 1H), 6.42 (s, 1H), 4.12 (d, J = 14.8 Hz, 1H), 3.85 (s,3H), 3.75 (d, J = 14.9 Hz, 1H), 1.23 (ddd, J = 13.2, 8.3, 5.0 Hz, 1H),0.96-0.87 (m, 2H), 0.75-0.70 (m, 2H), 0.67 (d, J = 8.3 Hz, 6H),0.25-0.17 (m, 2H), 0.02 (dt, J = 5.7, 4.5 Hz, 2H). 927 1H NMR (400 MHz,Methanol-d4) δ 8.50 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 6.2Hz, 1H), 7.81 (s, 1H), 7.71 (dd, J = 7.3, 1.2 Hz, 1H), 7.66 (d, J = 2.3Hz, 1H), 7.56-7.50 (m, 1H), 7.44 (d, J = 6.3 Hz, 1H), 6.82 (d, J = 2.3Hz, 1H), 6.66 (s, 1H), 4.32 (d, J = 14.8 Hz, 1H), 4.12 (s, 3H), 4.01 (d,J = 14.8 Hz, 1H), 1.61 (s, 3H), 1.27 (d, J = 4.9 Hz, 2H), 1.05-1.00 (m,2H), 0.93 (d, J = 9.1 Hz, 6H). 928 1H NMR (400 MHz, Methanol-d4) δ 8.50(s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.75 (s,1H), 7.70 (d, J = 7.4 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.56-7.49 (m,1H), 7.44 (dd, J = 6.3, 0.9 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.68 (s,1H), 4.30 (d, J = 14.8 Hz, 1H), 4.12 (s, 3H), 4.02 (d, J = 14.8 Hz, 1H),2.66 (s, 1H), 2.34 (s, 6H), 0.93 (d, J = 10.0 Hz, 6H). 929 1H NMR (400MHz, Methanol-d4) δ 8.47 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.04 (s,1H), 7.99 (d, J = 6.2 Hz, 1H), 7.78-7.72 (m, 1H), 7.67 (d, J = 2.3 Hz,1H), 7.54 (dd, J = 8.2, 7.4 Hz, 1H), 7.49-7.42 (m, 1H), 6.89 (d, J = 2.3Hz, 1H), 6.75 (s, 1H), 4.12 (s, 3H), 3.98 (d, J = 13.8 Hz, 1H), 3.66 (d,J = 13.8 Hz, 1H), 1.76-1.54 (m, 4H), 0.72 (s, 9H). 930 1H NMR (400 MHz,Methanol-d4) δ 8.48 (s, 1H), 8.39-8.32 (m, 1H), 8.01 (s, 1H), 7.82 (d, J= 8.4 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.62-7.55 (m, 1H), 7.42 (d, J =7.3 Hz, 1H), 6.98 (d, J = 9.2 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.77(s, 1H), 4.05 (s, 3H), 4.00 (d, J = 13.9 Hz, 1H), 3.67 (d, J = 13.8 Hz,1H), 1.77-1.55 (m, 4H), 0.74 (s, 9H). 931 1H NMR (400 MHz, Methanol-d4)δ 8.48 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H), 7.84(s, 1H), 7.75 (dd, J = 7.3, 1.1 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.53(dd, J = 8.3, 7.4 Hz, 1H), 7.45 (d, J = 6.2 Hz, 1H), 6.86 (d, J = 2.3Hz, 1H), 6.69 (s, 1H), 4.12 (s, 3H), 4.01 (d, J = 13.8 Hz, 1H), 3.63 (d,J = 13.8 Hz, 1H), 1.49 (ddd, J = 13.2, 8.3, 5.0 Hz, 1H), 1.23-1.13 (m,2H), 1.03-0.94 (m, 2H), 0.71 (s, 9H), 0.52-0.44 (m, 2H), 0.32-0.25 (m,2H). 932 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.27 (d, J = 8.3Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H), 7.78 (s, 1H), 7.76-7.72 (m, 1H), 7.68(d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.4, 7.3 Hz, 1H), 7.45 (dd, J = 6.3,0.9 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.72 (s, 1H), 5.03-4.90 (m, 1H),4.71 (d, J = 5.4 Hz, 1H), 4.62-4.56 (m, 1H), 4.12 (s, 3H), 4.01 (d, J =13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 1.51 (dd, J = 7.1, 1.3 Hz, 3H),0.72 (s, 9H). 933 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.28 (d,J = 8.1 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H), 7.85 (s, 1H), 7.75 (d, J =7.2 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.54 (dd, J = 8.4, 7.3 Hz, 1H),7.46 (dd, J = 6.3, 0.9 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.75 (s, 1H),5.31-5.12 (m, 1H), 4.99-4.86 (m, 2H), 4.83-4.71 (m, 2H), 4.01 (d, J =13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 0.72 (s, 11H). 934 1H NMR (400MHz, Methanol-d4) δ 8.46 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.99 (d, J =6.2 Hz, 1H), 7.89 (s, 1H), 7.71 (dd, J = 7.3, 1.1 Hz, 1H), 7.65 (d, J =2.3 Hz, 1H), 7.53 (dd, J = 8.3, 7.4 Hz, 1H), 7.45 (d, J = 6.3 Hz, 1H),6.82 (d, J = 2.3 Hz, 1H), 6.71 (s, 1H), 5.91 (t, J = 54.8 Hz, 1H), 4.28(d, J = 14.7 Hz, 1H), 4.12 (s, 3H), 4.00 (d, J = 14.7 Hz, 1H), 2.02 (s,1H), 1.49 (d, J = 4.5 Hz, 4H), 0.92 (d, J = 10.6 Hz, 6H). 935 1H NMR(400 MHz, Methanol-d4) δ 8.91 (s, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 8.18(d, J = 2.1 Hz, 1H), 8.04 (t, J = 2.2 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H),7.94 (d, J = 9.4 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.10 (d, J = 2.3 Hz,1H), 6.33 (s, 1H), 4.01 (d, J = 14.0 Hz, 1H), 3.75-3.61 (m, 1H), 2.03(s, 1H), 1.82-1.73 (m, 2H), 1.68 (s, 2H), 1.10 (s, 0H), 0.87 (s, 9H).936 1H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.20 (s, 1H),7.79-7.58 (m, 3H), 7.08 (d, J = 2.3 Hz, 1H), 6.39 (t, J = 6.9 Hz, 1H),6.19 (s, 1H), 4.17 (d, J = 14.0 Hz, 1H), 3.77 (d, J = 14.0 Hz, 1H), 3.59(s, 3H), 1.81-1.57 (m, 4H), 0.99 (s, 9H). 937 1H NMR (400 MHz,Methanol-d4) δ 8.88 (d, 1H), 8.45 (s, 1H), 8.25 (dd, 1H), 8.11 (s, 1H),8.10-8.02 (m, 1H), 7.73-7.66 (m, 3H), 6.90 (d, 1H), 6.76 (s, 1H),4.02-3.93 (m, 1H), 3.63 (d, 1H), 1.77-1.56 (m, 4H), 0.71 (s, 9H). 938 1HNMR (400 MHz, Chloroform-d) δ 8.99-8.81 (m, 1H), 8.23 (d, 1H), 8.14 (s,1H), 7.66-7.58 (m, 1H), 7.43 (d, 1H), 7.39-7.28 (m, 2H), 6.34 (s, 1H),6.08 (s, 1H), 4.00 (d, 1H), 3.64 (d, 1H), 2.47 (d, 3H), 1.80-1.61 (m,4H), 0.91 (d, 9H). 939 1H NMR (400 MHz, Acetonitrile-d3) δ 8.44 (s, 1H),8.30 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.63 (s, 1H), 7.54(s, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 6.78 (d, J= 7.7 Hz, 2H), 6.66 (s, 1H), 6.46 (s, 1H), 3.84 (dd, J = 13.5, 5.9 Hz,1H), 3.68 (dd, J = 13.2, 4.7 Hz, 1H), 3.54 (s, 3H), 2.08-1.99 (m, 6H),1.79 (m, 6H), 1.72 (m, 1H), 0.81 (s, 9H). 940 1H NMR (400 MHz,Methanol-d4) δ 9.06 (d, J = 4.7 Hz, 1H), 8.93 (d, J = 8.7 Hz, 1H), 8.48(s, 1H), 8.16-8.08 (m, 1H), 8.02 (s, 1H), 7.95-7.86 (m, 1H), 7.81 (t, J= 7.3 Hz, 2H), 7.68 (d, J = 2.3 Hz, 1H), 6.91-6.84 (m, 2H), 5.91 (t, J =54.7 Hz, 1H), 4.32 (d, J = 15.0 Hz, 1H), 3.96 (d, J = 14.9 Hz, 1H), 1.50(s, 4H), 0.96 (s, 3H), 0.91 (s, 3H). 941 1H NMR (400 MHz, Methanol-d4) δ8.48 (s, 1H), 8.13 (m, 2H), 7.68 (d, J = 2.1 Hz, 1H), 7.05 (s, 2H), 6.91(s, 1H), 6.10 (s, 1H), 4.22 (d, J = 13.9 Hz, 1H), 3.88 s, 3H), 3.68 (d,J = 13.9 Hz, 1H), 1.72 (d, J = 31.5 Hz, 4H), 0.97 (d, J = 1.0 Hz, 9H).942 1H NMR (400 MHz, Methanol-d4) δ 8.49 (d, J = 1.3 Hz, 1H), 7.82 (t, J= 8.1 Hz, 1H), 7.64 (dd, J = 2.3, 1.1 Hz, 1H), 6.97-6.82 (m, 1H), 6.77(d, J = 2.3 Hz, 1H), 6.17-5.79 (m, 2H), 4.44 (d, J = 15.0 Hz, 1H), 4.01(d, J = 14.9 Hz, 1H), 2.40 (s, 3H), 1.78-1.56 (m, 4H), 1.10 (d, J = 3.3Hz, 6H). 943 1H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.82 (t, J =8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 12.6, 2.6 Hz, 2H),6.08 (s, 1H), 4.12 (d, J = 13.9 Hz, 1H), 3.69 (d, J = 13.9 Hz, 1H), 2.40(s, 3H), 1.66-1.55 (m, 1H), 1.35-1.25 (m, 2H), 1.22-1.13 (m, 2H), 0.90(s, 9H), 0.55-0.46 (m, 2H), 0.43-0.32 (m, 2H). 944 1H NMR (400 MHz,Methanol-d4) δ 8.23 (s, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.51 (d, J = 2.4Hz, 1H), 6.93-6.82 (m, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.03 (s, 1H), 3.88(d, J = 13.7 Hz, 1H), 3.50 (d, J = 13.6 Hz, 1H), 2.73 (s, 1H), 2.61 (s,6H), 2.42 (s, 3H), 0.85 (s, 9H). 945 1H NMR (400 MHz, Methanol-d4) δ8.26 (s, 1H), 7.89 (t, J = 8.1 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 6.86(dd, J = 8.5, 2.6 Hz, 1H), 6.71 (s, 1H), 6.17-5.81 (m, 2H), 3.95 (d, J =13.8 Hz, 1H), 3.49 (d, J = 13.7 Hz, 1H), 2.39 (s, 3H), 1.69 (m, 2H),1.65-1.56 (m, 2H), 0.85 (s, 9H). 946 1H NMR (400 MHz, Methanol-d4) δ8.47 (s, 1H), 7.81 (t, J = 8.1 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 6.83(d, J = 6.3 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 6.08 (s, 1H), 4.14 (d, J= 13.8 Hz, 1H), 3.89-3.80 (m, 1H), 3.60 (d, J = 13.8 Hz, 1H), 2.37 (s,3H), 1.91-1.83 (m, 1H), 1.35-1.26 (m, 2H), 1.27-1.19 (m, 2H), 1.07 (dd,J = 8.7, 2.9 Hz, 2H), 0.91 (s, 1H), 0.87 (s, 9H), 0.84-0.77 (m, 1H). 9471H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H),7.62 (d, J = 2.2 Hz, 1H), 6.88 (q, J = 3.1 Hz, 2H), 6.17 (s, 1H), 4.05(d, J = 13.9 Hz, 1H), 3.75 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.60 (s,3H), 1.36-1.30 (m, 2H), 1.15-1.07 (m, 2H), 0.92 (s, 9H). 948 1H NMR (400MHz, Methanol-d4) δ 8.23 (d, J = 1.2 Hz, 1H), 7.88 (t, J = 8.1 Hz, 1H),7.51 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.5, 2.7 Hz, 1H), 6.70 (d, J =2.4 Hz, 1H), 6.17 (s, 1H), 5.90 (t, J = 54.3 Hz, 1H), 4.23 (d, J = 14.8Hz, 1H), 3.92 (d, J = 14.8 Hz, 1H), 2.49 (s, 3H), 1.66-1.43 (m, 4H),1.07 (d, J = 5.3 Hz, 6H). 949 1H NMR (400 MHz, Methanol-d4) δ 8.46 (s,1H), 7.86 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.88 (dd, J =8.1, 2.5 Hz, 2H), 6.18 (s, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.74 (d, J =13.9 Hz, 1H), 2.49 (s, 3H), 1.55-1.42 (m, 1H), 1.28-1.20 (m, 2H),1.11-1.03 (m, 2H), 0.92 (s, 10H), 0.57-0.46 (m, 2H), 0.35-0.28 (m, 2H).950 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.89 (t, J = 8.1 Hz,1H), 7.65 (d, J = 2.3 Hz, 1H), 7.42-7.26 (m, 5H), 7.16 (d, J = 2.3 Hz,1H), 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.36 (s, 1H), 5.78 (t, J = 7.2 Hz,1H), 2.52 (s, 3H), 2.14 (m, 2H), 1.81 (m, 2H), 1.74 (m, 2H), 1.02 (t, J= 7.3 Hz, 3H). 951 1H NMR (400 MHz, Methanol-d4) δ 8.52 (d, J = 0.8 Hz,1H), 7.87 (t, J = 8.1 Hz, 1H), 7.65 (dd, J = 2.3, 0.8 Hz, 1H), 6.94 (d,J = 2.3 Hz, 1H), 6.90 (dd, J = 8.4, 2.8 Hz, 1H), 6.19 (s, 1H), 4.06 (d,J = 13.9 Hz, 1H), 3.83 (d, J = 13.9 Hz, 1H), 2.75 (s, 1H), 2.52 (s, 3H),2.45 (s, 6H), 0.96 (s, 9H). 952 1H NMR (400 MHz, Methanol-d4) δ 8.51 (d,J = 0.9 Hz, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.66 (dd, J = 2.3, 0.9 Hz,1H), 6.95 (d, J = 2.3 Hz, 1H), 6.90 (dd, J = 8.6, 2.8 Hz, 1H), 6.23 (s,1H), 4.98-4.87 (m, 0H), 4.82-4.58 (m, 2H), 4.14-4.02 (m, 1H), 3.81 (d, J= 13.9 Hz, 1H), 2.51 (s, 3H), 1.66-1.55 (m, 3H), 0.95 (d, J = 0.9 Hz,9H). 953 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 7.92 (s, 1H),7.89 (t, J = 8.1 Hz, 1H), 7.78-7.72 (m, 1H), 7.65 (d, J = 2.3 Hz, 1H),7.03 (d, J = 2.4 Hz, 1H), 6.89 (dd, J = 8.5, 2.8 Hz, 1H), 6.12 (s, 1H),5.88 (t, J = 54.2 Hz, 1H), 2.45 (s, 3H), 1.56 (m, 4H). 954 1H NMR (400MHz, Methanol-d4) δ 8.37 (d, J = 1.5 Hz, 1H), 7.87 (t, J = 8.1 Hz, 1H),7.77 (d, J = 2.3 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.92-6.84 (m, 1H),6.18 (s, 1H), 3.90 (d, J = 13.9 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 2.73(s, 1H), 2.51 (s, 3H), 2.43 (s, 6H), 0.89 (s, 9H). 955 1H NMR (400 MHz,Methanol-d4) δ 8.50 (s, 1H), 7.83 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3Hz, 1H), 6.88 (dd, J = 9.0, 2.6 Hz, 2H), 6.19 (s, 1H), 4.99-4.88 (m,0H), 4.80-4.68 (m, 1H), 4.68-4.52 (m, 1H), 4.37 (d, J = 14.9 Hz, 1H),4.13 (d, J = 15.0 Hz, 1H), 2.49 (s, 3H), 1.59 (d, J = 1.4 Hz, 2H), 1.57(d, J = 1.4 Hz, 1H), 1.15 (s, 3H), 1.14 (s, 3H). 956 1H NMR (400 MHz,Methanol-d4) δ 8.51 (s, 1H), 7.83 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3Hz, 1H), 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.15(s, 1H), 4.34 (d, J = 15.0 Hz, 1H), 4.16 (d, J = 15.0 Hz, 1H), 2.72 (s,1H), 2.51 (s, 3H), 2.43 (s, 6H), 1.15 (s, 3H), 1.15 (s, 3H). 957 1H NMR(400 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.65(d, J = 2.3 Hz, 1H), 6.89 (d, J = 2.8 Hz, 1H), 6.86 (d, J = 2.2 Hz, 2H),6.17 (s, 1H), 4.41 (d, J = 15.0 Hz, 1H), 4.12 (d, J = 15.0 Hz, 1H), 2.49(s, 3H), 1.55-1.44 (m, 1H), 1.30-1.19 (m, 2H), 1.16 (s, 3H), 1.15 (s,3H), 1.08 (m, 2H), 0.58-0.45 (m, 2H), 0.38-0.28 (m, 2H). 958 1H NMR (400MHz, Methanol-d4) δ 8.48 (s, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.61 (d, J =2.3 Hz, 1H), 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H),6.15 (s, 1H), 4.34 (d, J = 15.0 Hz, 1H), 4.13 (d, J = 15.0 Hz, 1H),3.71-3.60 (m, 1H), 2.50 (s, 3H), 1.31-1.16 (m, 3H), 1.15 (s, 4H), 1.14(s, 3H). 959 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.84 (t, J =8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.5, 2.8 Hz, 1H),6.84 (d, J = 2.3 Hz, 1H), 6.15 (s, 1H), 4.39 (d, J = 15.0 Hz, 1H), 4.12(d, J = 15.0 Hz, 1H), 2.49 (s, 3H), 1.60 (s, 3H), 1.40-1.29 (m, 2H),1.15 (s, 3H), 1.14 (s, 3H), 1.12-1.06 (m, 2H). 960 1H NMR (400 MHz,Methanol-d4) δ 8.49 (s, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.4, 2.8 Hz, 1H), 6.22(s, 1H), 5.88 (t, J = 54.2 Hz, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.79 (d,J = 14.0 Hz, 1H), 2.50 (s, 3H), 1.58 (m, 4H), 0.94 (s, 9H). 961 1H NMR(400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.34 (dd, J = 8.1, 1.2 Hz, 1H),7.81-7.74 (m, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H),7.43 (d, J = 7.7 Hz, 1H), 6.83 (s, 1H), 6.82 (d, J = 4.5 Hz, 1H), 6.54(s, 1H), 4.01 (d, J = 13.8 Hz, 1H), 3.62 (d, J = 13.8 Hz, 1H), 3.61 (s,3H), 2.71 (s, 1H), 2.41 (s, 6H), 0.76 (s, 9H). 962 1H NMR (400 MHz,Acetonitrile-d3) δ 8.99-8.93 (m, 1H), 8.80 (d, J = 8.7 Hz, 1H), 8.31 (s,1H), 8.12 (d, J = 7.5 Hz, 1H), 7.83-7.72 (m, 2H), 7.66 (dd, J = 8.7, 4.7Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 6.69 (d, J = 3.0 Hz, 2H), 6.60 (s,1H), 6.30 (s, 1H), 5.69 (t, J = 54.1 Hz, 1H), 3.71 (dd, J = 13.5, 6.6Hz, 1H), 3.47 (dd, J = 13.5, 4.7 Hz, 1H), 1.88-1.82 (m, 3H), 1.43 (m,4H), 0.60 (s, 9H). 963 1H NMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H),7.89 (t, J = 8.1 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.5,2.7 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.15 (s, 1H), 3.94 (d, J = 1.2Hz, 3H), 3.84 (d, J = 13.7 Hz, 1H), 3.56 (d, J = 13.7 Hz, 1H), 2.51 (s,3H), 0.87 (s, 9H). 964 1H NMR (400 MHz, Methanol-d4) δ 8.33 (s, 1H),7.89 (t, J = 8.2 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 6.98 (d, J = 2.5 Hz,1H), 6.91-6.81 (m, 1H), 6.18 (s, 1H), 5.96 (t, J = 55.1 Hz, 1H), 4.06(s, 3H), 3.99 (d, J = 13.7 Hz, 1H), 3.45 (d, J = 13.8 Hz, 1H), 2.42 (s,3H), 1.54 (m, 2H), 1.50 (m, 2H), 0.85 (s, 9H). 965 1H NMR (400 MHz,Methanol-d4) δ 8.50 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.66 (d, J = 2.3Hz, 1H), 6.85 (m, 2H), 6.18 (s, 1H), 5.95 (t, J = 55.0 Hz, 1H), 4.17 (d,J = 13.9 Hz, 1H), 4.03 (s, 3H), 3.64 (d, J = 13.9 Hz, 1H), 2.43 (s, 3H),1.60-1.53 (m, 2H), 1.53-1.44 (m, 2H), 0.91 (s, 9H). 966 1H NMR (400 MHz,Methanol-d4) δ 8.50 (s, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 8.6Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.63 (d, J = 8.6 Hz, 1H), 6.14 (s,1H), 5.94 (t, J = 55.0 Hz, 1H), 4.13 (d, J = 13.9 Hz, 1H), 3.97 (s, 3H),3.90 (s, 3H), 3.73 (d, J = 13.9 Hz, 1H), 2.43 (s, 3H), 1.61-1.52 (m,2H), 1.52-1.42 (m, 2H), 0.93 (s, 9H). 967 1H NMR (400 MHz, Methanol-d4)δ 8.48 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.86(dd, J = 8.4, 2.7 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.12 (s, 1H), 4.11(d, J = 13.9 Hz, 1H), 3.91 (s, 3H), 3.69 (d, J = 13.9 Hz, 1H), 3.66-3.61(m, 1H), 2.45 (s, 3H), 1.31-1.20 (m, 1H), 1.20-1.12 (m, 2H), 0.91 (s,9H). 968 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.85 (t, J = 8.1Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.5, 2.8 Hz, 1H), 6.82(d, J = 2.3 Hz, 1H), 6.13 (s, 1H), 4.11 (d, J = 13.8 Hz, 1H), 3.88 (s,3H), 3.69 (d, J = 13.9 Hz, 1H), 2.70 (s, 1H), 2.44 (s, 3H), 2.43 (s,6H), 0.91 (s, 9H). 969 1H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H),7.90 (t, J = 8.1 Hz, 1H), 7.50 (d, J = 2.3 Hz, 1H), 6.85 (dd, J = 8.4,3.0 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 6.12 (s, 1H), 3.97-3.84 (m, 7H),3.43 (d, J = 13.7 Hz, 1H), 2.44 (s, 3H), 0.84 (s, 9H). 970 1H NMR (400MHz, Methanol-d4) δ 8.50 (s, 1H), 7.71-7.53 (m, 2H), 6.86 (d, J = 2.3Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 4.07 (d, J = 13.8 Hz, 1H), 3.88 (m,7H), 3.81 (s, 3H), 2.45 (s, 3H), 0.93 (s, 9H). 971 1H NMR (400 MHz,Methanol-d4) δ 8.46 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3Hz, 1H), 6.86 (dd, J = 8.5, 2.8 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.14(s, 1H), 4.10 (d, J = 13.9 Hz, 1H), 3.88 (m, 6H), 3.66 (d, J = 13.8 Hz,1H), 2.45 (s, 3H), 0.90 (s, 9H). 972 1H NMR (400 MHz, Methanol-d4) δ8.42 (s, 1H), 8.03 (s, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.49-7.38 (m,2H), 7.07 (s, 1H), 6.75 (s, 1H), 4.06 (d, 1H), 3.67 (d, 1H), 2.85-2.74(m, 1H), 1.74-1.57 (m, 4H), 0.83 (s, 9H). 973 1H NMR (400 MHz, DMSO-d6)δ 8.23 (s, 1H), 7.78 (t, J = 8.3 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H),6.98-6.75 (m, 2H), 6.27-5.84 (m, 2H), 2.42 (s, 3H), 1.47 (d, J = 3.4 Hz,4H), 0.76 (s, 9H). 974 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H),7.77 (t, J = 8.1 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.04 (d, J = 2.3 Hz,1H), 6.91 (dd, J = 8.5, 2.8 Hz, 1H), 6.43 (s, 1H), 5.92 (t, J = 53.7 Hz,1H), 3.95 (s, 2H), 2.54 (s, 3H), 1.81-1.62 (m, 4H), 0.95 (s, 9H). 975 1HNMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.91 (t, J = 8.3 Hz, 1H), 7.73(t, J = 5.5 Hz, 1H), 7.49 (s, 1H), 7.00 (dd, J = 8.5, 3.1 Hz, 1H), 6.47(s, 2H), 6.06 (t, J = 53.4 Hz, 1H), 3.61 (d, J = 5.5 Hz, 2H), 2.50 (s,3H), 1.56 (m, 4H), 1.05 (s, 9H). 976 1H NMR (400 MHz, Methanol-d4) δ9.31 (s, 1H), 8.94 (s, 2H), 8.38 (s, 1H), 8.06 (s, 1H), 7.82 (t, J = 8.1Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.87 (dd, J= 8.5, 2.7 Hz, 1H), 6.29 (s, 1H), 5.93 (t, J = 54.6 Hz, 1H), 4.04 (d, J= 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.51 (s, 3H), 1.53 (s, 4H),0.95 (s, 9H). 977 1H NMR (400 MHz, Methanol-d4) δ 8.51 (d, J = 1.1 Hz,1H), 7.81 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.86 (dd, J =8.6, 2.7 Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H), 6.07 (s, 1H), 4.13 (d, J =13.9 Hz, 1H), 3.70 (d, J = 13.9 Hz, 1H), 2.40 (s, 3H), 1.64 (s, 3H),1.44-1.31 (m, 2H), 1.22 (t, J = 2.0 Hz, 2H), 0.89 (s, 9H). 978 1H NMR(400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.11 (s, 1H), 7.62 (d, J = 2.3Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 6.96-6.89 (m, 1H), 6.60 (d, J = 8.6Hz, 1H), 6.19 (s, 1H), 3.98 (d, J = 13.9 Hz, 1H), 3.88 (d, J = 6.4 Hz,4H), 2.48 (s, 3H), 1.73 (d, J = 5.6 Hz, 2H), 1.66 (s, 2H), 0.94 (s, 9H).979 1H NMR (400 MHz, Methanol-d4) δ 8.55 (d, J = 1.6 Hz, 1H), 8.32 (s,1H), 7.88 (d, J = 2.6 Hz, 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.40 (d, J =2.6 Hz, 1H), 6.92 (dd, J = 8.5, 2.8 Hz, 1H), 6.76 (s, 1H), 4.09 (d, J =14.1 Hz, 1H), 3.96 (d, J = 14.1 Hz, 1H), 2.97 (s, 3H), 2.35 (s, 3H),1.80-1.70 (m, 4H), 1.02 (d, J = 3.2 Hz, 9H). 980 1H NMR (400 MHz,Chloroform-d) δ 8.36 (s, 1H), 7.91 (t, 1H), 7.48 (s, 1H), 7.33 (d, 1H),6.79 (dd, 1H), 6.40 (s, 1H), 5.94 (s, 1H), 5.20 (s, 1H), 3.56 (t, 2H),3.33 (s, 3H), 2.59 (s, 3H), 1.79 (d, 6H), 1.77-1.70 (m, 1H), 1.68-1.50(m, 4H) 0.94 (s, 9H). 981 1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H),8.29 (d, J = 2.4 Hz, 1H), 8.08 (s, 1H), 7.81 (t, J = 8.1 Hz, 1H), 7.18(d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.29 (s, 1H), 5.93(t, J = 54.6 Hz, 1H), 4.05 (d, J = 14.0 Hz, 1H), 3.87 (d, J = 14.0 Hz,1H), 2.77 (s, 3H), 2.52 (s, 3H), 1.54 (s, 4H), 0.94 (s, 9H). 982 1H NMR(400 MHz, Chloroform-d) δ 10.32 (s, 1H), 9.20 (s, 1H), 8.30-8.20 (m,1H), 8.13 (s, 1H), 7.90 (t, 1H), 7.19 (s, 1H), 6.82-6.65 (m, 2H), 6.24(s, 1H), 4.17-4.02 (m, 2H), 2.64 (s, 3H), 1.78 (s, 3H), 1.77 (s, 3H),1.72-1.63 (m, 4H), 1.09 (s, 9H). 983 1H NMR (400 MHz, DMSO-d6) δ 8.73(s, 1H), 8.17 (t, 1H), 8.01 (s, 1H), 7.98-7.93 (m, 1H); 7.06 (dd, 1H),6.70 (s, 1H), 6.52-6.43 (m, 1H), 6.09 (t, 1H), 3.67 (qd, 2H), 2.43 (s,3H), 1.52-1.40 (m, 4H), 0.95 (s, 9H). 984 1H NMR (400 MHz, Methanol-d4)δ 8.47 (s, 1H), 7.85 (s, 1H), 7.77 (m, 1H), 7.62 (s, 1H), 6.87 (m, 2H),6.20 (s, 1H), 4.38 (t, J = 7.4 Hz, 2H), 4.01 (d, J = 13.9 Hz, 1H), 3.80(d, J = 13.7 Hz, 1H), 2.50 (m, 5H), 1.89-1.80 (m, 2H), 1.29 (m, 2H),0.92 (s, 11H). 985 1H NMR (400 MHz, Acetonitrile-d3) δ 8.41 (s, 1H),7.84 (m, 1H), 7.66 (m, 1H), 7.48 (m, 1H), 6.82 (m, 1H), 6.74 (m, 1H),6.15 (m, 1H), 4.42 (m, 2H), 3.76 (m, 2H), 3.48 (m, 2H), 2.51 (s, 3H),1.98 (m, 2H), 0.94 (s, 9H). 986 1H NMR (400 MHz, Acetonitrile-d3) δ 8.42(s, 1H), 7.92 (m, 1H), 7.48 (s, 1H), 6.79 (m, 1H), 6.70 (s, 1H), 5.97(s, 1H), 4.35 (m, 4H), 3.90 (m, 1H), 3.68 (m, 1H), 2.50 (s, 3H), 2.23(m, 2H), 0.94 (s, 9H).

Biological Assays

The following examples, from Examples 40 to 42, describe biologicalassays for measuring certain test compounds' activity against TNFα, Cot(also known as Tpl2), and EGFR. As summarized in Table 3, the testcompounds are effective inhibitors of Cot.

Example 40 Cot Monocyte TNFα Cell Based Assay

Cryopreserved human monocytes (Stem Cell Technologies) were thawed,diluted in RPMI with Glutamax (10 mM HEPES, 1× Pen-Strep, 55 M1-mercaptoethanol, 1 mM Sodium pyruvate) media containing 10% FBS to0.125×10̂6 cells/ml and recovered at 37° C. for 2 hours. The cellsuspension was then plated at a density of 5,000 cells/well onto black384 well Greiner clear bottom plates. Plates were pre-spotted with testcompounds and serially diluted in DMSO where 200 nL/well were deliveredusing the Echo 550 acoustic liquid dispenser (Labcyte®) for a final DMSOconcentration of 0.5%. Plated cells were treated with compound for 1hour at 37° C. Cells were then stimulated with 50 pg/ml of LPS (Sigma)excluding outside columns of plate used for unstimulated cell controlwells. Cells were incubated for an additional 4 hours at 37° C. Cellswere then spun out of the media and 5 μl of sample were taken andanalyzed for total TNFα content using the TR-FRET Human TNFα detectionsystem (CisBio). This system utilizes two labeled antibodies (cryptateand XL665) that bind to two different epitopes of the TNFα molecule andproduce FRET signal proportional to the concentration of TNFα in thesample. Detection antibodies are mixed 50:50 and 5 μL were dispensedinto each well. Plates were covered with clear seals and incubated atroom temp overnight. The following morning plates were read using anEnvision 2103 Multilabeled reader (PerkinElmer) withexcitation/emission/FRET emission at 340 nm/615 nm/665 nm, respectively.Fluorescence intensities at 615 nm and 665 nm emission wavelengths wereexpressed as a ratio (665 nm/615 nm). Percent of control was calculatedas follows:

%Control=100×(Ratio_(Sample)−Ratio_(0% stimulation))/(Ratio_(100% Stimulation)−Ratio_(0% Stimulation))

where unstimulated cells (0% stimulation) were the negative control andstimulated cells (100% stimulation) were used as the positive control.

Example 41 High Throughput Cot Biochemical Assay

Human Cot enzyme activity was measured using KinEASE (Cisbio), atime-resolved fluorescence resonance energy transfer (TR-FRET)immunoassay. In this assay, Cot-catalyzes the phosporylation of aXL665-labeled peptide substrate. Europium conjugated phospho-tyrosinespecific antibody binds the resulting phosphorylated peptide. Formationof phosphorylated peptide is quantified by TR-FRET with Europium as thedonor and XL665 the acceptor in a 2-step endpoint assay. Purifiedrecombinant human Cot catalytic domain (30-397 amino acids) waspurchased from Carna Biosciences. In brief, test compounds seriallydiluted in DMSO were delivered into Proxy white, low volume, 384 wellplates using the Echo 550 acoustic liquid dispenser (Labcyte®). Cotenzyme and substrates were dispensed into assay plates using a Multi-Flo(Bio-Tek Instruments). The standard 5 μL reaction mixture contained 400μM ATP, 1 μM STK3 peptide, 5 nM of Cot in reaction buffer (10 mM MOPS,pH 7.0, 0.02% NaN₃, 0.5 mg/mL BSA, 10 mM MgOAc, 1 mM DTT, 0.025% NP-40,1.5% glycerol) and 0.1% DMSO. After 2.5 hrs of incubation at roomtemperature, 5 μL of Stop and Detect Solution (1:200 Europium Cryptatelabeled anti-phosphorylated peptide antibody solution and 125 nMstrepavidin-XL665 Tracer in a 50 mM Hepes pH 7.0 detection buffercontaining sufficient EDTA) was added. The plate was then furtherincubated for 120 minutes at room temperature and read using an Envision2103 Multilabeled reader (PerkinElmer) with excitation/emission/FRETemission at 340 nm/615 nm/665 nm, respectively. Fluorescence intensitiesat 615 nm and 665 nm emission wavelengths were expressed as a ratio (665nm/615 nm). Percent inhibition was calculated as follows:

%Inhibition=100×(Ratio_(Sample)−Ratio_(0% Inhibition))/(Ratio_(100% Inhibition)−Ratio_(0% Inhibition))

where 0.1% DMSO (0% inhibition) was the negative control and 100 μMComparative Example 1 (100% inhibition) was used as the positivecontrol.

Example 42 High Throughput EGFR Biochemical Assay

EGFR activity was measured using KinEASE (Cisbio), a time-resolvedfluorescence resonance energy transfer (TR-FRET) immunoassay. In thisassay, EGFR-catalyzes the phosphorylation of a universal Tyrosine kinasepeptide substrate labeled with XL665. Europium conjugatedphosphor-tyrosine specific antibody binds the resulting phosphorylatedpeptide. Formation of phosphorylated peptide is quantified by TR-FRETwith Europium as the donor and XL665 the acceptor. The assay wasperformed in two main steps. The first step is the kinase reaction stepand the second step is the detection step with TR-FRET reagents. Inbrief, test compounds 1:3 serially diluted in DMSO were delivered intoCorning white, low volume, non-binding 384 well plates using the Echo550 acoustic liquid dispenser (Labcyte®). EGFR enzyme (Human EGFR,cytoplasmic domain [669-1210] from Carna Biosciences Cat. No. 08-115)and substrates TK substrate-biotin (included in Cisbio HTRF KinEASE-TKkit Cat. No. 62TK0PEJ) were dispensed into assay plates using aMulti-Flo (Bio-Tek Instruments). The standard 10 μL reaction mixturecontained 6 μM ATP (1×Km) or 12 μM ATP (2×Km), 1 μM biotinylatedpeptide, 0.3 nM EGFR (for 1×Km ATP) or 0.1 nM EGFR (for 2×Km ATP) inreaction buffer (10 mM MOPs, pH 7.0, 1.5% Glycerol, 0.5 mg/ml BSA, 10 mMMg-Acetate, 1 mM DTT, 0.025% NP-40). After 60 min of incubation at roomtemperature, 10 μL of Stop and Detect Solution (1:400 Europium Cryptatelabeled anti-phosphorylated peptide antibody solution and 125 nMstrepavidin-XL665 Tracer in a 50 mM Hepes pH 7.0 detection buffercontaining sufficient EDTA) was added. The plate was then furtherincubated for over 60 minutes at room temperature and read using anEnvision 2103 Multilabeled reader (PerkinElmer) withexcitation/emission/FRET emission at 340 nm/615 nm/665 nm, respectively.Fluorescence intensities at 615 nm and 665 nm emission wavelengths wereexpressed as a ratio (665 nm/615 nm). Percent inhibition was calculatedas follows:

%Inhibition=100×(Ratio_(Sample)−Ratio_(0% Inhibition))/(Ratio_(100% Inhibition)−Ratio_(0% Inhibition))

where 0.05% DMSO (0% inhibition) was the negative control and 100 μMStaurosporine and Gefitinib (100% inhibition) was used as the positivecontrol.

As shown in Table 3, the compounds of Formula I are inhibitors of Cot(cancer Osaka thyroid).

TABLE 3 Cmpd IC₅₀ HTRF (nM) EC₅₀ TNF (nM) 1 8 218 2 2 89 3 8 314 4 2 4975 9 258 7 380 >1000 8 7 302 9 1 20 10 21 283 11 4 154 12 27 214 13 11765 14 7 196 15 2 545 16 2 115 17 53 1388 18 28 399 19 2 156 20 2 69 2114 2035 22 2 89 23 4 69 24 12 185 25 2 57 26 6 113 27 2 62 28 12 195 2917 498 30 34 1322 31 5 5069 32 7 546 33 11 630 34 8 112 35 9 166 36 3 6737 16 2638 38 25 952 39 11 295 40 6 249 41 8 137 42 135 1926 43 33 91544 9 129 45 2 178 46 3 1102 47 25 1068 48 2 87 49 118 16684 50 70 353451 55 1556 52 4 88 53 81 4018 54 11 652 55 58 10816 56 6 2521 57 60 599058 72 2982 59 2 892 60 12 131 61 11 238 62 10 216 63 5 257 64 42 2652 656 538 66 3 53 67 1 32 68 1 51 69 2 33 70 19 804 71 2 36 72 1 11 73 2 3374 1 14 75 2 79 76 1 981 77 3 154 78 3 332 79 1 203 80 1 23 81 400 >100082 2 151 83 942 1000 84 1 10 85 4 >1000 86 2 37 87 25 590 88 1161 >100089 520 >1000 90 1 18 91 2 52 92 6 65 93 7 74 94 2 130 95 10 445 96 11173 97 20 358 98 49 821 99 3 143 100 3 142 101 5 348 102 3 461 103 3 133104 1 99 105 3 144 106 2 76 107 182 >10000 108 913 >10000 109 2 54 110 256 111 2 77 112 2 61 113 13 253 114 10 233 115 5 119 116 3 144 117 3 94118 6 150 119 4 99 120 5 137 121 7 171 122 6 240 123 6 193 124 8 376 1253 78 126 3 146 127 16 194 128 698 >10000 129 2 81 130 6 147 131 2 49 1324 97 133 25 978 134 6 197 135 23 660 136 10 291 137 15 235 138 3 141 1392 92 140 3 183 141 2 121 142 2 66 143 16 898 144 2 77 145 4 221 146 10370 147 12 1139 148 5 174 149 8 381 150 4 154 151 8 1305 152 10 904 15344 3759 154 26 1667 155 2 79 156 8 1191 157 5 127 159 2 95 160 11 484161 12 1668 162 7 429 163 67 4142 164 5 1802 165 9 2368 166 6 1425 167 4506 168 6 394 169 14 1217 170 6 1262 171 10 320 172 10 832 173 7 1112174 2 54 175 3 73 176 2 31 177 2 79 178 7 931 179 265 >10000 180 1 104181 2 92 182 13 1041 183 357 >10000 184 8 387 185 305 9745 186 118 6618187 67 2114 188 >10000 >10000 189 8 1061 190 9 238 191 2 104 192 3 186193 2 107 194 2 111 195 4 132 196 6 668 197 9 599 198 17 982 199 9 2522200 7 558 201 56 5595 202 >10000 >10000 203 6923 9089 204 8513 >10000205 72 2048 206 3 211 207 5 931 208 12 465 209 23 941 210 10 424 211 16544 212 44 9151 213 3 103 214 >10000 >10000 215 258 >10000 216 38 1187217 12 264 218 26 2711 219 4449 >10000 220 4 348 221 2 28 222 19 739 2237 94 224 12 2628 225 10 1488 226 8 880 227 44 6419 228 18 2307 229 121467 230 9 252 231 8 230 232 15 346 233 8 114 234 21 504 235 17 370 2369 172 237 1 29 238 3 901 239 16 928 240 16 631 241 2 32 242 143 5801 24341 9492 244 4 328 245 2 125 246 6 652 247 2 102 248 4 398 249 12 332 2505 127 251 5 347 252 6 119 253 4 66 254 3 230 255 10 766 256 16 341 257 6212 258 2 33 259 6 158 260 6 126 261 14 344 262 11 130 263 13 242 264 270 265 14 426 266 37 28752 267 30 5120 268 12 234 269 6 326 270 4 666271 9 826 272 5 297 273 51 1564 274 12 370 275 7 2334 276 6 789 277 7923 278 3 269 279 3 457 280 16 811 281 13 575 282 3 87 283 3 50 284 141305 285 8 219 286 4 121 287 20 373 288 26 1058 289 37 837 290 12 185291 35 478 292 17 327 294 9 166 295 23 565 296 80 1104 297 9 200 298 391503 299 18 739 300 7 165 301 14 414 302 10 472 303 14 868 304 6 234 3053 84 306 6 202 307 4 60 308 4 286 309 8 181 310 40 2342 312 13 1235 3135 373 314 15 302 315 4 132 316 6 298 317 16 251 318 8 271 319 5 165 32110 212 322 33 369 323 86 666 325 20 650 326 34 3753 328 4 272 331 3 173334 4 82 335 10 405 339 13 1010 340 8 328 341 6 843 342 38 6094 344 3151 345 3 73 346 3 208 347 4 278 348 13 444 349 41 718 350 26 4511 35110 744 352 12 565 353 4 184 354 3 983 355 5 194 357 5 235 358 3 130 3593 729 360 4 151 361 13 746 362 1 46 363 4 257 364 7 241 366 5 336 367 13338 368 649 6296 369 3 89 370 8 232 371 2 173 372 2 81 373 3 81 374 37480 375 4 1511 376 182 >1000 377 398 >1000 378 2 168 379 6 179 380 14609 381 7 303 382 14 768 389 11 328 395 4 403 9 290 405 2 1044 406 3 1026 2 293 32 311 30 320 60 324 10 327 15 329 14 330 59 332 65 333 3 336 2337 16 338 13 343 504 356 2 365 38 384 153 385 14 386 36 387 18 388 10390 343 391 282 392 3 393 5 394 147 396 43 397 46 398 435 399 58 400 119401 10 402 19 404 232 408 1 88 409 1 559 410 113 1000 411 5 76 412 7 157413 4 44 414 1 35 415 3 67 416 2 124 417 9 218 418 2 45 419 3 49 420 225 421 4 100 422 2 57 423 3 71 424 2 37 425 7 1000 426 2 95 427 2 41 4281 69 429 2 56 430 5 214 431 1 21 432 6 89 433 1 65 434 2 61 435 1 24 4365 289 437 2 82 438 473 1000 439 13 299 440 7 171 441 2 26 442 56 2686443 1 19 444 2 33 445 2 71 446 3 156 447 2 40 448 2 44 449 19 407 450 20356 451 3 138 452 4 73 453 9 184 454 2 32 455 29 222 456 51 1000 457 3151000 458 4 87 459 3 50 460 5 156 461 17 154 462 162 8766 463 2 63 464 116 465 2 155 466 28 926 467 2 47 468 1 18 469 4 69 470 2 46 471 3 45 4724 78 473 2 26 474 2 26 475 20 258 476 3 71 477 2 185 478 1 77 479 5 78480 2 60 481 6 391 482 3 86 483 7 108 484 3 73 485 3 29 486 3 991 487 1245 488 3 79 489 2 129 490 1 1000 491 3 40 492 2 21 493 31 1000 494 1444 495 3 50 496 6 467 497 6 379 498 19 689 499 3 97 500 8 321 501 3 55502 6 206 503 2 45 504 1 38 505 5 277 506 8 528 507 2 87 508 4 96 509267 1000 510 5 222 511 6 133 512 10 418 513 9 154 514 4 77 515 199 1000516 2 34 517 3 1000 518 7 207 519 3 158 520 123 926 521 27 256 522 5 52523 2 63 524 12 77 525 4 164 526 5 73 527 3 78 528 3 60 529 2 50 530 370 531 3 70 532 3 78 533 3 96 534 20 394 535 2 47 536 3 51 537 2 75 5385 109 539 1 12 540 50 760 541 6 180 542 2 40 543 13 422 544 8 210 545 4108 546 2 42 547 2 33 548 8 124 549 4 68 550 2 29 551 2 27 552 2 26 5533 64 554 5 151 555 7 208 556 8 120 557 5 117 558 3 72 559 2 42 560 11287 561 2 433 562 2 231 563 2 63 564 3 69 565 2 306 566 2 190 567 2 66568 5 170 569 7 171 570 184 1000 571 2 77 572 4 79 573 66 751 574 4 86575 1 974 576 1 433 577 1 49 578 2 32 579 2 24 580 2 84 581 2 32 582 14184 583 4 121 584 2 53 585 37 838 586 2 1000 587 1 489 588 55 629 589 234 590 3 57 591 5 106 592 5 78 593 8 298 594 2 33 595 209 1000 596 79826 597 3 150 598 5 198 599 13 316 600 5 113 601 4 32 602 3 69 603 7 107604 3 71 605 3 30 606 2 27 607 21 225 608 42 314 609 2 46 610 2 199 61120 229 612 11 171 613 13 144 614 9 154 615 33 588 616 12 104 617 9 77618 3 37 619 7 189 620 102 1000 621 1 12 622 1 24 623 1 27 624 11 1000625 2 26 626 5 35 627 4 46 628 450 1000 629 181 1000 630 68 1000 631 232 632 380 1000 633 28 267 634 2 43 635 3 60 636 69 720 637 3 85 638 58858 639 58 806 640 3 65 641 55 811 642 5 182 643 5 1000 644 7 88 645 1166 646 3 40 647 3 133 648 3 114 649 2 14 650 179 1000 651 14 135 652 440 653 4 37 654 3 36 655 12 104 656 4 86 657 37 806 658 29 374 659 41279 660 43 839 661 2 103 662 6 335 663 3 62 664 12 154 665 6 198 666 13246 667 10 71 668 13 408 669 1 7 670 5 102 671 2 32 672 2 22 673 142 808674 22 301 675 1 7 676 6 112 677 4 133 678 5 131 679 13 710 680 3 98 6812 26 682 7 66 683 35 283 684 14 101 685 4 39 686 4 77 687 15 178 688 30437 689 9 81 690 21 250 691 6 66 692 3 38 693 15 141 694 7 84 695 3 39696 2 14 697 1 11 698 27 684 699 12 386 700 2 179 701 10 147 702 4 188703 2 22 704 1 23 705 6 61 706 2 14 707 16 230 708 6 176 709 17 187 7105 148 711 2 32 713 2 21 714 6 57 715 3 91 716 2 54 717 8 100 718 9 112719 2 24 720 2 35 721 6 109 722 43 403 723 4 84 724 3 44 725 3 56 726 4127 727 3 48 728 7 154 729 5 108 730 10 89 731 11 179 732 11 779 733 42835 734 41 313 735 47 478 736 117 645 737 3 91 738 2 40 739 21 254 74045 311 741 6 120 742 17 199 743 5 116 744 3 33 745 2 28 746 13 178 747 436 748 5 47 749 6 66 750 11 194 751 15 230 752 5 57 753 5 59 754 3 31755 25 365 756 3 26 757 5 60 758 4 50 759 2 42 760 2 58 761 6 69 762 350 763 3 40 764 4 46 765 4 131 766 2 30 767 18 209 768 6 86 769 2 28 7704 108 771 4 293 772 2 33 773 2 35 774 2 40 775 3 27 776 2 24 111 5 46778 4 30 779 3 26 780 5 52 781 2 22 782 23 177 783 2 23 784 3 51 785 223 786 5 47 787 2 65 788 23 208 789 13 156 790 5 82 791 22 242 792 89843 793 35 782 794 15 130 795 34 530 796 2 31 797 3 77 798 7 90 799 4 46800 2 25 801 3 31 802 4 36 803 7 97 804 9 137 805 28 778 806 3 28 807 331 808 3 29 809 3 32 810 4 54 811 11 333 812 5 68 813 2 24 814 2 16 8153 39 816 1 23 817 10 116 818 6 176 819 2 28 820 3 33 821 3 60 822 10 687823 4 53 824 5 59 825 7 113 826 51 1000 827 2 38 828 22 253 829 4 66 83016 384 831 8 202 832 2 44 833 2 22 834 5 68 835 4 53 836 4 52 837 7 121838 3 84 839 6 94 840 4 52 841 2 41 842 3 563 843 4 104 844 13 417 84520 1000 846 2 17 847 31 296 848 31 247 849 16 261 850 6 65 851 3 21 8522 58 853 1 98 854 4 17 855 2 53 856 1 29 857 4 180 858 7 44 859 2 53 8603 31 861 7 40 862 8 49 863 2 35 864 2 37 865 4 23 866 2 18 867 3 27 8682 70 869 2 37 870 2 169 871 1 32 872 1 15 873 5 97 874 3 73 875 2 166876 2 385 877 2 34 878 2 31 879 1 13 880 3 80 881 2 13 882 2 18 883 1 13884 1 19 885 10 132 886 3 30 887 3 33 888 2 165 889 9 104 890 6 68 891 112 892 2 44 893 4 99 894 3 54 895 3 41 896 3 30 897 2 18 898 5 56 899 229 900 3 30 901 484 1000 902 3 36 903 3 36 904 5 78 905 15 212 906 4 39907 4 51 908 12 238 909 8 116 910 5 148 911 7 85 912 6 78 913 6 86 914 9116 915 44 324 916 13 269 917 3 31 918 3 42 919 2 49 920 3 28 921 17 187922 11 225 923 16 258 926 13 174 927 6 124 928 6 99 929 11 157 930 33504 931 10 134 932 14 205 933 29 247 934 7 81 935 24 424 936 18 287 93723 277 938 26 223 939 18 104 940 7 86 941 64 804 945 17 142 946 5 153947 3 39 948 5 99 949 4 34 950 17 260 951 9 61 952 4 36 953 36 353 954 716 955 6 50 956 7 44 957 5 54 958 2 56 959 3 41 960 7 55 961 3 48 962 13135 963 4 51 964 3 105 965 4 78 966 15 191 967 2 94 968 2 94 969 8 258970 34 722 971 11 301 972 1817 1000 973 3 34 974 11 60 975 1231 1000 97621 276 978 9 303 979 244 1000 980 1000 1000 981 4 20 982 1000 1000 9839644 1000 984 10 169 985 13 126 986 5 141

The data in Table 4 and Table 5 shows that the compounds disclosedherein are effective inhibitors of cancer Osaka thyroid (Cot). Inaddition, the claimed compounds are not significant EGFR ligands.

TABLE 4 IC₅₀/EC₅₀ EGFR (IC₅₀) Compound Compound Structure [nM] [nM]Comparative Example 1

4/310  357 Comparative Example 2

62/NA NA 362

1/46  3984

TABLE 5 IC₅₀/EC₅₀ EGFR (IC₅₀) Compound Compound Structure [nM] [nM]Comparative Example 3

67/>10000 >10000 Comparative Example 4

>10000/Na >10000 395

4/NA  NA 406

3/102 >10000

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20170008905A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A compound of Formula I:

wherein R¹ is hydrogen, —O—R⁷, —N(R⁸)(R⁹), —C(O)—R⁷, —S(O)₂—R⁷, —C₁₋₉alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl,or heteroaryl; wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionallysubstituted with one to four Z¹; R² is hydrogen, —C(O)—R⁷, —C(O)O—R⁷,—C(O)N(R⁷)₂, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein each C₁₋₉alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,aryl, heterocyclyl, and heteroaryl may be optionally substituted withone to four Z²; or R¹ and R² together with the nitrogen to which theyare attached to form a heterocyclyl or heteroaryl, wherein eachheterocyclyl or heteroaryl is optionally substituted with one to fourZ²; R³ is heterocyclyl or heteroaryl, wherein each heterocyclyl orheteroaryl is optionally substituted with one to four Z³; R⁴ isheterocyclyl or heteroaryl, wherein each heterocyclyl or heteroaryl isoptionally substituted with one to four Z⁴; R⁵ is hydrogen, halo, —CN,—NO₂, —O—R⁷, —N(R⁸)(R⁹), —S(O)—R⁷, —S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷,—OC(O)—R⁷, —C(O)O—R⁷, —OC(O)O—R⁷, —OC(O)N(R¹⁰)(R¹¹), —C(O)N(R⁷)₂,—N(R⁷)C(O)(R⁷), C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio,C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl;wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio,C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl maybe optionally substituted with one to four Z⁵; R⁶ is hydrogen, —C(O)—R⁷,—C(O)O—R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl; whereineach C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅cycloalkyl, aryl, heterocyclyl, and heteroaryl may be optionallysubstituted with one to four Z⁶; each R⁷ is independently hydrogen, C₁₋₉alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,aryl, heterocyclyl, or heteroaryl; wherein each C₁₋₉ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,heterocyclyl, and heteroaryl may be optionally substituted with one tofour Z⁷; R⁸ and R⁹ at each occurrence are independently hydrogen,—S(O)₂R¹⁰, —C(O)—R¹⁰, —C(O)O—R¹⁰, —C(O)N(R¹⁰)(R¹¹), C₁₋₉ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,heterocyclyl, or heteroaryl; wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, orheteroaryl may be optionally substituted with one to four Z⁸; R¹⁰ andR¹¹ at each occurrence are independently hydrogen, C₁₋₉ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,heterocyclyl, or heteroaryl, wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, andheteroaryl optionally is substituted with one to four Z^(1b); each Z¹,Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, and Z⁸ is independently hydrogen, oxo, halo,—NO₂, —N₃, —CN, thioxo, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹²,—C(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,—N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹³)(R¹⁴),—N(R¹²)S(O)₂(R¹²), —NR¹²S(O)₂N(R¹³)(R¹⁴), —NR¹²S(O)₂O(R¹²), —OC(O)R¹²,—OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂, —OP(O)(OR¹²)₂, —CH₂P(O)(OR¹²)₂,—OCH₂P(O)(OR¹²)₂, —C(O)OCH₂P(O)(OR¹²)₂, —P(O)(R¹²)(OR¹²),—OP(O)(R¹²)(OR¹²), —CH₂P(O)(R¹²)(R¹²)(OR¹²), —OCH₂P(O)(R¹²)(OR¹²),—C(O)OCH₂P(O)(R¹²)(OR¹²), —P(O)(N(R¹²)₂)₂, —OP(O)(N(R¹²)₂)₂,—CH₂P(O)(N(R¹²)₂)₂, —OCH₂P(O)(N(R¹²)₂)₂, —C(O)OCH₂P(O)(N(R¹²)₂)₂,—P(O)(N(R¹²)₂)(OR¹²), —OP(O)(N(R¹²)₂)(OR¹²), —CH₂P(O)(N(R¹²)₂)(OR¹²),—OCH₂P(O)(N(R¹²)₂)(OR¹²), —C(O)OCH₂P(O)(N(R¹²)₂)(OR¹²),—P(O)(R¹²)(N(R¹²)₂), —OP(O)(R¹²)(N(R¹²)₂), —CH₂P(O)(R¹²)(N(R¹²)₂),—OCH₂P(O)(R¹²)(N(R¹²)₂), —C(O)OCH₂P(O)(R¹²)(N(R¹²)₂), —Si(R¹²)₃, —S—R¹²,—S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴); wherein anyalkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl orheterocyclyl is optionally substituted with one to four Z^(1a) groups;each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃, C₁₋₉alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl,aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹², —C(O)O—R¹²,—C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, —N(R¹²)—C(O)R¹²,—N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹³)(R¹⁴), —N(R¹²)S(O)₂(R¹²),—N(R¹²)S(O)₂—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹²,—OC(O)—N(R¹³)(R¹⁴), —Si(R¹²)₃, —S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹²or —S(O)₂N(R¹³)(R¹⁴); wherein any alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl or heterocyclyl is optionally substituted with one tofour Z^(1b) groups; each R¹² is independently hydrogen, C₁₋₉ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl orheterocyclyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl or heterocyclyl is optionally substituted with one to fourZ^(1b) groups; R¹³ and R¹⁴ at each occurrence are each independentlyhydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl,aryl, heteroaryl or heterocyclyl; wherein any alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substitutedwith one to four Z^(1b) groups, or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a heterocyclyl, wherein saidheterocyclyl is optionally substituted with one to four Z^(1b) groups;each R¹⁵ is independently halo, —CN, —NO₂, —O—R⁷, —N(R⁸)(R⁹), —S(O)—R⁷,—S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷, —OC(O)O—R⁷,—OC(O)N(R¹⁰)(R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,aryl, heterocyclyl, or heteroaryl; and each Z^(1b) is independently oxo,thioxo, hydroxy, halo, —NO₂, —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl,heterocyclyl, —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl),—O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl), —O(heteroaryl),—O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl), —NH(C₂₋₆alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl),—NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,—N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₂₋₆alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈ haloalkyl), —N(C₁₋₉ alkyl)(aryl),—N(C₁₋₉ alkyl)(heteroaryl), —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉alkyl), —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅cycloalkyl), —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl), —C(O)(heteroaryl),—C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl), —C(O)O(C₂₋₆ alkenyl),—C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅ cycloalkyl), —C(O)O(C₁₋₈ haloalkyl),—C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂,—C(O)NH(C₁₋₉ alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),—C(O)NH(C₃₋₁₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl), —C(O)NH(aryl),—C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆ alkynyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂, —C(O)N(aryl)₂,—C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂, —NHC(O)(C₁₋₉ alkyl),—NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆ alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl),—NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),—NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl),—NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl),—NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),—NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl), —S(C₂₋₆ alkenyl), —S(C₂₋₆alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈ haloalkyl), —S(aryl),—S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl), —N(C₁₋₉alkyl)(S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉ alkyl),—S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆ alkynyl),—S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁₋₈ haloalkyl), —S(O)(aryl),—S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₂₋₆alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈haloalkyl), —S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl),—S(O)₂NH(C₁₋₉ alkyl), or —S(O)₂N(C₁₋₉ alkyl)₂; wherein any alkyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substitutedwith one to four halo, C₁₋₉ alkyl, C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉alkyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl),—NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),—NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),—NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉ alkyl),—S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl),—S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉alkyl), —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),—O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl); m is 0,1, or 2; or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof. 2-18. (canceled)
 19. Acompound of Formula VIIIA:

wherein R¹ is hydrogen, —C(O)—R⁷, —S(O)₂—R⁷, —C₁₋₉ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, or heteroaryl;wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₅ cycloalkyl,heterocyclyl, aryl, and heteroaryl may be optionally substituted withone to four Z¹; R⁴ is heterocyclyl or heteroaryl, wherein eachheterocyclyl or heteroaryl is optionally substituted with one to fourZ⁴; R⁵ is hydrogen, halo, —CN, —NO₂, —O—R⁷, —N(R⁸)(R⁹), —S(O)—R⁷,—S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷, —OC(O)O—R⁷,—OC(O)N(R¹)(R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,heterocyclyl, or heteroaryl; wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₉ alkylthio, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,heterocyclyl, and heteroaryl may be optionally substituted with one tofour Z⁵; R⁶ is hydrogen, —C(O)—R⁷, —C(O)O—R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,heterocyclyl, or heteroaryl; wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, andheteroaryl may be optionally substituted with one to four Z⁶; each R⁷ isindependently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl; whereineach C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅cycloalkyl, aryl, heterocyclyl, and heteroaryl may be optionallysubstituted with one to four Z⁷; R⁸ and R⁹ at each occurrence areindependently hydrogen, —S(O)₂R¹⁰, —C(O)—R¹⁰, —C(O)O—R¹⁰,—C(O)N(R¹⁰)(R¹¹), C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl; whereineach C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅cycloalkyl, aryl, heterocyclyl, or heteroaryl may be optionallysubstituted with one to four Z⁸; R¹⁰ and R¹¹ at each occurrence areindependently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl, whereineach C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅cycloalkyl, aryl, heterocyclyl, and heteroaryl optionally is substitutedwith one to four Z^(1b); each Z¹, Z⁴, Z⁵, Z⁶, Z⁷, and Z⁸ isindependently hydrogen, oxo, halo, —NO₂, —N₃, —CN, thioxo, C₁₋₉ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ Cycloalkyl, C₁₋₈ haloalkyl, aryl,heteroaryl, heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹²,—C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, —N(R¹²)C(O)—R¹²,—N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹³)(R¹⁴), —N(R¹²)S(O)(R¹²),—NR¹²S(O)₂N(R¹³)(R¹⁴), —NR¹²S(O)₂O(R¹²), —OC(O)R¹², —OC(O)—N(R¹³)(R¹⁴),—P(O)(OR¹²)₂, —OP(O)(OR¹²)₂, —CH₂P(O)(OR¹²)₂, —OCH₂P(O)(OR¹²)₂,—C(O)OCH₂P(O)(OR¹²)₂, —P(O)(R¹²)(OR¹²), —OP(O)(R¹²)(OR¹²),—CH₂P(O)(R¹²)(OR¹²), —OCH₂P(O)(R¹²)(OR¹²), —C(O)OCH₂P(O)(R¹²)(OR¹²),—P(O)(N(R¹²)₂, —OP(O)(N(R¹²)₂, —CH₂P(O)(N(R¹²)₂, —OCH₂P(O)(N(R¹²)₂)₂,—C(O)OCH₂P(O)(N(R¹²)₂)₂, —P(O)(N(R¹²)₂)(OR¹²), —OP(O)(N(R¹²)₂)(OR¹²),—CH₂P(O)(N(R¹²)₂)(OR¹²), OCH₂P(O)(N(R¹²)₂)(OR¹²),—C(O)OCH₂P(O)(N(R¹²)₂)(OR¹²), —P(O)(R¹²)(N(R¹²)₂), —OP(O)(R¹²)(N(R¹²)₂),—CH₂P(O)(R¹²)(N(R¹²)₂), —OCH₂P(O)(R²)N(R¹²)₂),—C(O)OCH₂P(O)(R²)(N(R¹²)₂), —Si(R¹²)₃, —S—R¹², —S(O)R¹², —S(O)(NH)R¹²,—S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴); wherein any alkyl, alkenyl, alkynyl,cycloalkyl, haloalkyl, aryl, heteroaryl or heterocyclyl is optionallysubstituted with one to four Z^(1a) groups; each Z^(1a) is independentlyoxo, halo, thioxo, —NO₂, —CN, —N₃, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl,heterocyclyl, —O—R¹², —C(O)R¹², —C(O)O—R¹², —C(O)N(R¹³)(R¹⁴),—N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, —N(R¹²)—C(O)R¹², —N(R¹²)C(O)O(R¹²),—N(R¹²)C(O)N(R¹³)(R¹⁴), —N(R¹²)S(O)₂(R¹²), —N(R¹²)S(O)₂—N(R¹³)(R¹⁴),—N(R¹²)S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹³)(R¹⁴),—Si(R¹²)₃, —S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S()₂N(R¹³)(R¹⁴); wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl or heterocyclyl is optionally substituted with one to fourZ^(1b) groups; each R¹² is independently hydrogen, C₁₋₉ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl orheterocyclyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl or heterocyclyl is optionally substituted with one to fourZ^(1b) groups; R¹³ and R¹⁴ at each occurrence are each independentlyhydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl,aryl, heteroaryl or heterocyclyl; wherein any alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substitutedwith one to four Z^(1b) groups, or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a heterocyclyl, wherein saidheterocyclyl is optionally substituted with one to four Z^(1b) groups;and, each Z^(1b) is independently oxo, thioxo, hydroxy, halo, —NO₂, —N₃,—CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈haloalkyl, aryl, heteroaryl, heterocyclyl, —O(C₁₋₉ alkyl), —O(C₂₋₆alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),—O(aryl), —O(heteroaryl), —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl),—NH(C₂₋₆ alkenyl), —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈haloalkyl), —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉alkyl)₂, —N(C₃₋₁₅ cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂,—N(C₃₋₁₅ cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,—N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₂₋₆alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈ haloalkyl), —N(C₁₋₉ alkyl)(aryl),—N(C₁₋₉ alkyl)(heteroaryl), —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉alkyl), —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅cycloalkyl), —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl), —C(O)(heteroaryl),—C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl), —C(O)O(C₂₋₆ alkenyl),—C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅ cycloalkyl), —C(O)O(C₁₋₈ haloalkyl),—C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂,—C(O)NH(C₁₋₉ alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),—C(O)NH(C₃₋₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl), —C(O)NH(aryl),—C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆ alkynyl)₂,—C(O)N(C₃₋₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂, —C(O)N(aryl)₂,—C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂, —NHC(O) (C₁₋₉ alkyl),—NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆ alkynyl), —NHC(O)(C₃₋₅ cycloalkyl),—NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),—NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl),—NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl),—NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),—NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl), —S(C₂₋₆ alkenyl), —S(C₂₋₆alkynyl), —S(C₃₋₅ cycloalkyl), —S(C₁₋₈ haloalkyl), —S(aryl),—S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl), —N(C₁₋₉alkyl)(S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉ alkyl),—S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₆ alkenyl), —S(O)(C₂₋₆ alkynyl),—S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁₋₈ haloalkyl), —S(O)(aryl),—S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂C₁₋₉ alkyl), —S(O)₂(C₂₋₆alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁shaloalkyl), —S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl),—S(O)₂NH(C₁₋₉ alkyl), or —S(O)₂N(C₁₋₉ alkyl)₂; wherein any alkyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substitutedwith one to four halo, C₁₋₉ alkyl, C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉alkyl), —NH(C₃₋₁₅cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl),—NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),—NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),—NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉ alkyl),—S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl),—S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉alkyl), —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),—O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl); and, Z⁹is hydrogen, halo, —CN, or —O—R¹²; or a pharmaceutically acceptablesalt, stereoisomer, mixture of stereoisomers or deuterated analogthereof.
 20. The compound of claim 19, wherein: Z³ is hydrogen, C₁₋₉alkyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein saidC₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, or heterocyclyl may be optionallysubstituted with one to four substituents independently selected fromthe group consisting of oxo, —CN, halo, —O—R¹², —C(O)—R¹², —C(O)O—R¹²,—OC(O)—R¹², —C(O)—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂(R¹²), —N(R¹³)(R¹⁴),—N(R¹³)₂(R¹⁴)⁺, —C(O)N(R¹²)—S(O)₂R¹², C₁₋₉ alkyl, C₁₋₈ haloalkyl, C₁₋₈hydroxyalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl; Z⁹is hydrogen; R¹ is C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, orheteroaryl; wherein said C₁₋₉ alkyl, heterocyclyl, aryl, or heteroarylmay be optionally substituted with one to three substituentsindependently selected the group consisting of halo, —CN, —O—R¹²,—S(O)₂R¹², C₁₋₉ alkyl, C₁₋₉ haloalkyl, heterocyclyl, and aryl, whereinsaid C₃₋₁₅ cycloalkyl may be optionally substituted with one to foursubstituents independently selected the group consisting of C₁₋₉ alkyl,and C₁₋₉ haloalkyl; R⁴ is heterocyclyl or heteroaryl; wherein saidheterocyclyl or heteroaryl is optionally substituted with one to threesubstituents independently selected from the group consisting of —CN,halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl, C₁₋₉ haloalkyl, andheterocyclyl; R⁵ is —CN, halo, —O—R⁷ or —S(O)₂R⁷; R⁶ is hydrogen; eachR⁷ is independently hydrogen or C₁₋₉ alkyl; wherein said C₁₋₉ alkyl maybe optionally substituted with one to three substituents independentlyselected from the group consisting of hydroxyl, halo, —O(C₁₋₉ alkyl) andaryl; each R¹² is independently hydrogen, C₁₋₉ alkyl or heterocyclyl;wherein said C₁₋₉ alkyl may be optionally substituted with one to threesubstituents independently selected from the group consisting ofhydroxyl, halo, —O(C₁₋₉ alkyl) and aryl; and each R¹³ and R¹⁴ isindependently hydrogen or C₁₋₉ alkyl; wherein said C₁₋₉ alkyl may beoptionally substituted with one to three substituents independentlyselected from the group consisting of hydroxyl, halo, —O(C₁₋₉ alkyl) andaryl; or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers thereof. 21-22. (canceled)
 23. The compound of claim 19,wherein R⁵ is cyano or halo, or a pharmaceutically acceptable saltthereof.
 24. The compound of claim 19, wherein R⁶ is hydrogen, or apharmaceutically acceptable salt thereof.
 25. The compound of claim 19,wherein R⁴ is heterocyclyl or heteroaryl; and said heterocyclyl orheteroaryl is optionally substituted with one to three substituentsindependently selected from the group consisting of —CN, halo, —O—R¹²,—C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl, C₁₋₉ haloalkyl, and heterocyclyl,or a pharmaceutically acceptable salt thereof.
 26. The compound of claim25, wherein R⁴ is heteroaryl optionally substituted with one to threesubstituents independently selected from the group consisting of —CN,halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl, C₁₋₉ haloalkyl, andheterocyclyl, or a pharmaceutically acceptable salt thereof.
 27. Thecompound of claim 25, wherein R⁴ is heterocyclyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of —CN, halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl,C₁₋₉ haloalkyl, and heterocyclyl, or a pharmaceutically acceptable saltthereof.
 28. (canceled)
 29. The compound of claim 19, wherein R⁴ is

and q is 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof.30. The compound of claim 29, wherein R⁴ is

or a pharmaceutically acceptable salt thereof.
 31. The compound of anyone of claim 30, wherein each Z⁴ is independently selected from thegroup consisting of —CN, halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉alkyl, C₁₋₉ haloalkyl, and heterocyclyl, or a pharmaceuticallyacceptable salt thereof.
 32. The compound of claim 19, wherein R⁴ is


33. A compound selected from Table 1, or a pharmaceutically acceptablesalt thereof; TABLE 1 Compound No. Structure  1

 2

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34. A composition comprising a compound of claim 19 and apharmaceutically acceptable carrier.
 35. A composition comprising amixture of stereoisomers of a compound of Formula I:

wherein the mixture comprises compounds of Formula IA and IB in a ratioof at least about 3:1:

wherein m, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁵ are as defined in claim 19.36. A method for treating a disease or condition mediated by cancerOsaka thyroid (Cot) in a human patient in need thereof, comprisingadministering to the patient an effective amount of the composition ofclaim
 34. 37. The method of claim 36, wherein the disease or conditionis cancer.
 38. The method of claim 36, wherein the disease or conditionis diabetes.
 39. The method of claim 36, wherein the disease orcondition is an inflammatory disease.
 40. The method of claim 36,wherein the disease or condition is inflammatory bowel disease.
 41. Acompound having the formula:

or a pharmaceutically acceptable salt thereof.
 42. A compositioncomprising a compound according to claim 41 and a pharmaceuticallyacceptable carrier.
 43. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 44. A compositioncomprising a compound according to claim 43 and a pharmaceuticallyacceptable carrier.
 45. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 46. A compositioncomprising a compound according to claim 45 and a pharmaceuticallyacceptable carrier.
 47. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 48. A compositioncomprising a compound according to claim 47 and a pharmaceuticallyacceptable carrier.
 49. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 50. A compositioncomprising a compound according to claim 49 and a pharmaceuticallyacceptable carrier.
 51. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 52. A compositioncomprising a compound according to claim 51 and a pharmaceuticallyacceptable carrier.
 53. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 54. A compositioncomprising a compound according to claim 53 and a pharmaceuticallyacceptable carrier. 55-59. (canceled)
 60. The method according to claim36 wherein said disease or condition is a solid tumor selected frompancreatic cancer, bladder cancer, colorectal cancer, breast cancer,prostate cancer, renal cancer, hepatocellular cancer, lung cancer,ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, headand neck cancer, melanoma, neuroendocrine cancers, CNS cancers, braintumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastomamultiforme, and adult anaplastic astrocytoma), bone cancer, and softtissue sarcoma.
 61. The method according to claim 36 wherein saiddisease or condition is selected from type 1 and type 2 diabetes,gestational diabetes, prediabetes, insulin resistance, metabolicsyndrome, impaired fasting glycaemia and impaired glucose tolerance. 62.The method according to claim 36 wherein said disease or condition isselected from systemic lupus erythematosus (SLE), myestenia gravis,rheumatoid arthritis (RA), acute disseminated encephalomyelitis,idiopathic thrombocytopenic purpura, multiple sclerosis (MS),inflammatory bowel disease (IBD), sepsis, psoriasis, Sjoegren'ssyndrome, autoimmune hemolytic anemia, asthma, or chronic obstructivepulmonary disease (COPD), ankylosing spondylitis, reactive arthritis,monoarticular arthritis, osteoarthritis, gouty arthritis, juvenilearthritis, juvenile onset rheumatoid arthritis, juvenile rheumatoidarthritis, and psoriatic arthritis.
 63. The method according to claim 36wherein said disease or condition is selected from diversion colitis,ischemic colitis, infectious colitis, chemical colitis, microscopiccolitis (including collagenous colitis and lymphocytic colitis),atypical colitis, pseudomembranous colitis, fulminant colitis, autisticenterocolitis, indeterminate colitis, Behçet's disease, gastroduodenalCD, jejunoileitis, ileitis, ileocolitis, Crohn's (granulomatous)colitis, irritable bowel syndrome, mucositis, radiation inducedenteritis, short bowel syndrome, celiac disease, stomach ulcers,diverticulitis, pouchitis, proctitis, and chronic diarrhea.
 64. Themethod according to claim 36 wherein said disease or condition isalcoholic hepatitis.
 65. The method according to claim 36 wherein saiddisease or condition is selected from systemic lupus erythematosus(SLE), lupus nephritis, lupus-related, and autoimmune disorders or asymptom of SLE.
 66. The method according to claim 65 wherein saidsymptom of SLE is selected from joint pain, joint swelling, arthritis,fatigue, hair loss, mouth sores, swollen lymph nodes, sensitivity tosunlight, skin rash, headaches, numbness, tingling, seizures, visionproblems, personality changes, abdominal pain, nausea, vomiting,abnormal heart rhythms, coughing up blood and difficulty breathing,patchy skin color and Raynaud's phenomenon.